Benzoimidazolyl-pyrazine compounds for inflammation and immune-related uses

ABSTRACT

Biologically active chemical compounds, namely benzoimidazolyl-pyrazine derivatives and structurally related compounds, are disclosed herein. Such compounds include those represented by structural formula (II): 
                         
and as described in further detail within. These compounds are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 60/784,037, filed Mar. 20, 2006, the entire contents ofwhich are incorporated herein by this reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT

Not applicable.

INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC

Not applicable.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

This invention relates to biologically active chemical compounds, namelybenzoimidazolyl-pyrazine derivatives and structurally related compoundsthat are used for immunosuppression or to treat or prevent inflammatoryconditions, allergic disorders and immune disorders.

(2) Description of Related Art

Not applicable.

Inflammation is a mechanism that protects mammals from invadingpathogens. However, while transient inflammation is necessary to protecta mammal from infection, uncontrolled inflammation causes tissue damageand is the underlying cause of many illnesses. Inflammation is typicallyinitiated by binding of an antigen to T-cell antigen receptor. Antigenbinding by a T-cell initiates calcium influx into the cell via calciumion channels, such as Ca²⁺-release-activated Ca²⁺ channels (CRAC).Calcium ion influx in turn initiates a signaling cascade that leads toactivation of these cells and an inflammatory response characterized bycytokine production.

Interleukin 2 (IL-2) is a cytokine that is secreted by T cells inresponse to calcium ion influx into the cell. IL-2 modulatesimmunological effects on many cells of the immune system. For example,it is a potent T cell mitogen that is required for T cell proliferation,promoting their progression from G1 to S phase of the cell cycle; itstimulates the growth of NK cells; and it acts as a growth factor to Bcells and stimulates antibody synthesis.

IL-2, although useful in the immune response, can cause a variety ofproblems. IL-2 damages the blood-brain barrier and the endothelium ofbrain vessels. These effects may be the underlying causes ofneuropsychiatric side effects observed under IL-2 therapy, e.g. fatigue,disorientation and depression. It also alters the electrophysiologicalbehaviour of neurons.

Due to its effects on both T and B cells, IL-2 is a major centralregulator of immune responses. It plays a role in inflammatoryreactions, tumour surveillance, and hematopoiesis. It also affects theproduction of other cytokines, inducing IL-1, TNF-α and TNF-β secretion,as well as stimulating the synthesis of IFN-γ in peripheral leukocytes.

T cells that are unable to produce IL-2 become inactive (anergic). Thisrenders them potentially inert to any antigenic stimulation they mightreceive in the future. As a result, agents which inhibit IL-2 productioncan be used for immunosupression or to treat or prevent inflammation andimmune disorders. This approach has been clinically validated withimmunosuppressive drugs such as cyclosporin, FK506, and RS61443. Despitethis proof of concept, agents that inhibit IL-2 production remain farfrom ideal. Among other problems, efficacy limitations and unwanted sideeffects (including dose-dependant nephrotoxicity and hypertension)hinder their use.

Over production of proinflammatory cytokines other than IL-2 has alsobeen implicated in many autoimmune diseases. For example, Interleukin 5(IL-5), a cytokine that increases the production of eosinophils, isincreased in asthma. Overproduction of IL-5 is associated withaccumulation of eosinophils in the asthmatic bronchial mucosa, a hallmark of allergic inflammation. Thus, patients with asthma and otherinflammatory disorders involving the accumulation of eosinophils wouldbenefit from the development of new drugs that inhibit the production ofIL-5.

Interleukin 4 (IL-4) and interleukin 13 (IL-13) have been identified asmediators of the hypercontractility of smooth muscle found ininflammatory bowel disease and asthma. Thus, patients with athsma andinflammatory bowel disease would benefit from the development of newdrugs that inhibit IL-4 and IL-13 production.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a regulatorof maturation of granulocyte and macrophage lineage population and hasbeen implicated as a key factor in inflammatory and autoimmune diseases.Anti-GM-CSF antibody blockade has been shown to ameliorate autoimmunedisease. Thus, development of new drugs that inhibit the production ofGM-CSF would be beneficial to patients with an inflammatory orautoimmune disease.

There is a continuing need for new drugs which overcome one or more ofthe shortcomings of drugs currently used for immunosuppression or in thetreatment or prevention of inflammatory disorders, allergic disordersand autoimmune disorders. Desirable properties of new drugs includeefficacy against diseases or disorders that are currently untreatable orpoorly treatable, new mechanism of action, oral bioavailability and/orreduced side effects.

BRIEF SUMMARY OF THE INVENTION

This invention meets the above-mentioned needs by providing certaincyclohexenyl-phenyl derivatives that inhibit the activity of CRAC ionchannels and inhibit the production of IL-2, IL-4, IL-5, IL-13, GM-CSF,TNF-α, and IFNγ. These compounds are particularly useful forimmunosuppression and/or to treat or prevent inflammatory conditions,allergic disorders and immune disorders.

In one embodiment, the invention relates to compounds represented bystructural formula (I):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁, X₂, and X₃ are, independently, CH, CR₁, or N;    -   L is a linker;    -   Y is an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, or an optionally substituted heteroaryl;    -   each Z is independently selected from the group consisting of a        lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower        alkyl sulfanyl, cyano, nitro, —N(R)₂, —NRC(O)R, —C(O)N(R)₂, or        lower haloalkoxy;    -   R, for each occurrence, is independently, H or a lower alkyl;    -   R₁, for each occurrence, is an independently selected        substituent;    -   R₄ is H or a substituent;    -   m is 0, 1, or 2; and    -   n is 0, 1 or 2.

In another embodiment, the invention relates to compounds represented bystructural formula (II):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   Y, L, Z, and n are defined as for formula (I);    -   R₉ is a lower alkyl, a halo, a lower haloalkyl, a lower alkoxy,        a lower haloalkoxy, —OH, —C(O)OR, —N(R)₂, —C(O)N(R)₂, —OC(O)R,        —NRC(O)R, or an optionally substituted heteroaryl; and    -   R₁₀ a halo, a lower alkyl, a lower haloalkyl, a lower alkoxy, or        a lower alkylsulfanyl.

In another embodiment, the invention relates to compounds represented bystructural formula (III):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   L, Y, Z, R, R₁, R₄, m, and n are defined as for formula (I);    -   ring A is aromatic or non-aromatic; and    -   X₅ is CH, CR₁, or N.

In another embodiment, the invention relates to compounds represented bystructural formula (IV):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   Y, L, Z, and n are defined as for formula (IV); and    -   R₁₀ is defined as for formula (II).

In another embodiment, the invention relates to compounds represented bystructural formula (V):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   Y, L, Z, and n are defined as for formula (IV); and    -   R₁₀ is defined as for formula (II).

In another embodiment, the invention relates to compounds represented bystructural formula (VI):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   Y, L, Z, and n are defined as for formula (IV); and    -   R₁₀ is defined as for formula (II).

A compound of the invention or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof is particularly useful inhibitingimmune cell (e.g., mast cells, T-cells and/or B-cells) activation (e.g.,cytokine production and/or proliferation in response to an antigen; andor mast cell degranulation). In particular, a compound of the inventionor a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof can inhibit the production of certain cytokines that regulateimmune cell activation. For example, a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereofcan inhibit the production of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α,INF-γ or combinations thereof. Moreover, a compound of the invention ora pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof can modulate the activity of one or more ion channel involved inactivation of immune cells, such as CRAC ion channels.

In one embodiment, compounds of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof are particularlyuseful for inhibiting mast cell degranulation. Mast cell degranulationhas been implicated in allergic reactions.

A compound of the invention or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof is particularly useful forimmunosuppression or for treating or preventing inflammatory conditions,allergic disorders, and immune disorders.

The invention also encompasses pharmaceutical compositions comprising acompound of the invention or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof; and a pharmaceuticallyacceptable carrier or vehicle. These compositions may further compriseadditional agents. These compositions are useful for immunosuppressionand treating or preventing inflammatory conditions, allergic disordersand immune disorders.

The invention further encompasses methods for treating or preventinginflammatory conditions, allergic disorders, and immune disorders,comprising administering to a subject in need thereof an effectiveamount of a compound of the invention or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, or a pharmaceuticalcomposition comprising a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof. These methodsmay also comprise administering to the subject an additional agentseparately or in a combination composition with the compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof.

The invention further encompasses methods for suppressing the immunesystem of a subject, comprising administering to a subject in needthereof an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, or a pharmaceutical composition comprising a compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof. These methods may also comprise administering to thesubject an additional agent separately or in a combination compositionwith the compound of the invention or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof.

The invention further encompasses methods for inhibiting immune cellactivation, including inhibiting proliferation of T cells and/or Bcells, in vivo or in vitro comprising administering to the cell aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof or apharmaceutical composition comprising a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

The invention further encompasses methods for inhibiting cytokineproduction in a cell (e.g., IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α,and/or INF-γ production) in vivo or in vitro comprising administering toa cell an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereofor a pharmaceutical composition comprising a compound of the inventionor a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

The invention further encompasses methods for modulating ion channelactivity (e.g., CRAC channel activity) in vivo or in vitro comprisingadministering an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereofor a pharmaceutical composition comprising a compound of the inventionor a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

All of the methods of this invention may be practice with a compound ofthe invention alone, or in combination with other agents, such as otherimmunosuppressive agents, anti-inflammatory agents, agents for thetreatment of allergic disorders or agents for the treatment of immunedisorders.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

FIG. 1 is a graph of the difference in ear weight between one earchallenged with ovalbumin and a second ear on the same animal treatedwith a saline solution. Ovalbumin caused swelling of the ear compared totreatment with a saline solution. Treatment with Compound 1 decreasedthe amount of swelling and thereby decreased ear weight compared toanimals treated with vehicle alone.

FIG. 2 is a graph showing ear weight of vehicle treated control animalsthat have been challenged with ovalbumin compared with animals that havebeen treated with Compound 1 then challenged with ovalbumin. Treatmentwith Compound 1 decreased the amount of swelling compared to animalstreated with vehicle alone and thereby decreased ear weight in treatedanimals.

FIG. 3 is a graph of the difference in ear thickness between one earchallenged with ovalbumin and a second ear on the same animal treatedwith a saline solution. Treatment with Compound 1 decreased the amountof swelling and thereby decreased ear thickness compared to animalstreated with vehicle alone.

FIG. 4 is a graph showing ear thickness of vehicle treated controlanimals that have been challenged with ovalbumin compared with animalsthat have been treated with Compound 1 then challenged with ovalbumin.Treatment with Compound 1 decreased the amount of swelling compared toanimals treated with vehicle alone and thereby decreased ear thicknessin treated animals.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise specified, the below terms used herein are defined asfollows:

As used herein, the term “aryl” means a monocyclic orpolycyclic-aromatic ring or ring radical comprising carbon and hydrogenatoms. Examples of suitable aryl groups include, but are not limited to,phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, and naphthyl,as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted orsubstituted with one or more substituents (including without limitationalkyl (preferably, lower alkyl or alkyl substituted with one or morehalo), hydroxy, alkoxy (preferably, lower alkoxy), alkylsulfanyl, cyano,halo, amino, and nitro. In certain embodiments, the aryl group is amonocyclic ring, wherein the ring comprises 6 carbon atoms.

As used herein, the term “alkyl” means a saturated straight chain orbranched non-cyclic hydrocarbon typically having from 1 to 10 carbonatoms. Representative saturated straight chain alkyls include methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyland n-decyl; while saturated branched alkyls include isopropyl,sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl,3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl,2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl,3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl,2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Alkylgroups included in compounds of this invention may be optionallysubstituted with one or more substituents. Examples of substituentsinclude, but are not limited to, amino, alkylamino, alkoxy,alkylsulfanyl, oxo, halo, acyl, nitro, hydroxyl, cyano, aryl, alkylaryl,aryloxy, arylsulfanyl, arylamino, carbocyclyl, carbocyclyloxy,carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy,heterocyclylamino, heterocyclylthio, and the like. In addition, anycarbon in the alkyl segment may be substituted with oxygen (═O), sulfur(═S), or nitrogen (═NR²², wherein R²² is —H, an alkyl, acetyl, oraralkyl). Lower alkyls are typically preferred for the compounds of thisinvention.

The term alkylene refers to an alkyl group or a cycloalkyl group thathas two points of attachment to two moieties (e.g., {—CH₂—}, —{CH₂CH₂—},

etc., wherein the brackets indicate the points of attachment). Alkylenegroups may be unsubstituted or substituted with one or moresubstituents.

An aralkyl group refers to an aryl group that is attached to anothermoiety via an alkylene linker. Aralkyl groups can be unsubstituted orsubstituted with one or more substituents.

The term “alkoxy,” as used herein, refers to an alkyl group which islinked to another moiety though an oxygen atom. Alkoxy groups can beunsubstituted or substituted with one or more substituents.

The term “alkylsulfanyl,” as used herein, refers to an alkyl group whichis linked to another moiety though a divalent sulfur atom. Alkylsulfanylgroups can be unsubstituted or substituted with one or moresubstituents.

The term “arylsulfanyl,” as used herein, refers to an aryl group whichis linked to another moiety though a divalent sulfur atom. Arylsulfanylgroups can be unsubstituted or substituted with one or moresubstituents.

The term “alkyl ester” as used herein, refers to a group represented bythe formula —C(O)OR₃₂, wherein R₃₂ is an alkyl group. A lower alkylester is a group represented by the formula —C(O)OR₃₂, wherein R₃₂ is alower alkyl group.

The term “heteroalkyl,” as used herein, refers to an alkyl group whichhas one or more carbons in the alkyl chain replaced with an —O—, —S— or—NR₂₇—, wherein R₂₇ is H or a lower alkyl. Heteroalkyl groups can beunsubstituted or substituted with one or more substituents.

The term “alkylamino,” as used herein, refers to an amino group in whichone hydrogen atom attached to the nitrogen has been replaced by an alkylgroup. The term “dialkylamino,” as used herein, refers to an amino groupin which two hydrogen atoms attached to the nitrogen have been replacedby alkyl groups, in which the alkyl groups can be the same or different.Alkylamino groups and dialkylamino groups can be unsubstituted orsubstituted with one or more substituents.

As used herein, the term “alkenyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at least one carbon-carbon double bond. Representative straightchain and branched alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl,isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,1-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl,3-decenyl and the like. Alkenyl groups can be unsubstituted orsubstituted with one or more substituents.

As used herein, the term “alkynyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at lease one carbon-carbon triple bond. Representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,4-pentynyl,-1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl,6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl,8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl and the like. Alkynyl groupscan be unsubstituted or substituted with one or more substituents.

As used herein, the term “cycloalkyl” means a saturated, mono- orpolycyclic alkyl radical typically having from 3 to 14 carbon atoms.Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly,decahydronaphthyl, octahydropentalene, bicycle[1.1.1]pentanyl, and thelike. Cycloalkyl groups can be unsubstituted or substituted with one ormore substituents.

As used herein, the term “cycloalkenyl” means a mono- or polycyclic,non-aromatic alkenyl ring having at least one carbon-carbon double bondin the cyclic system and typically having from 5 to 14 carbon atoms.Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl,cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl,cyclodecadienyl and the like. Cycloalkenyl groups can be unsubstitutedor substituted with one or more substituents.

As used herein, the term “heterocyclyl” means a monocyclic or polycyclicheterocyclic ring (typically having 3- to 14-members) which is either asaturated ring or an unsaturated non-aromatic ring. A 3-memberedheterocyclyl can contain up to 3 heteroatoms, and a 4- to 14-memberedheterocyclyl can contain from 1 to about 8 heteroatoms. Each heteroatomis independently selected from nitrogen, which can be quaternized;oxygen; and sulfur, including sulfoxide and sulfone. The heterocyclylmay be attached via any heteroatom or carbon atom. Representativeheterocyclyls include morpholinyl, thiomorpholinyl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl,oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 4H-pyranyl,tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like. A heteroatom may be substitutedwith a protecting group known to those of ordinary skill in the art, forexample, the hydrogen on a nitrogen may be substituted with atert-butoxycarbonyl group. Furthermore, the heterocyclyl may beoptionally substituted with one or more substituents (including withoutlimitation a halo, an alkyl, a haloalkyl, or aryl). Only stable isomersof such substituted heterocyclic groups are contemplated in thisdefinition.

As used herein, the term “heteroaryl” means a monocyclic or polycyclicheteroaromatic ring (or radical thereof) comprising carbon atom ringmembers and one or more heteroatom ring members (such as, for example,oxygen, sulfur or nitrogen). Typically, the heteroaromatic ring has from5 to about 14 ring members in which at least 1 ring member is aheteroatom selected from oxygen, sulfur and nitrogen. In anotherembodiment, the heteroaromatic ring is a 5 or 6 membered ring and maycontain from 1 to about 4 heteroatoms. In another embodiment, theheteroaromatic ring system has a 7 to 14 ring members and may containfrom 1 to about 7 heteroatoms. Representative heteroaryls includepyridyl, furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, indolizinyl,thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl, thiadiazolyl,pyrazinyl, quinolyl, isoquniolyl, indazolyl, benzoxazolyl, benzofuryl,benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl, tetrazolyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl,qunizaolinyl, purinyl, pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl orbenzo[b]thienyl and the like. Heteroaryl groups may be optionallysubstituted with one or more substituents.

A heteroaralkyl group refers to a heteroaryl group that is attached toanother moiety via an alkylene linker. Heteroaralkyl groups can beunsubstituted or substituted with one or more substituents.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

As used herein, the term “haloalkyl” means an alkyl group in which oneor more —H is replaced with a halo group. Examples of haloalkyl groupsinclude —CF₃, —CHF₂, —CCl₃, —CH₂CH₂Br, —CH₂CH(CH₂CH₂Br)CH₃, —CHICH₃, andthe like.

As used herein, the term “haloalkoxy” means an alkoxy group in which oneor more —H is replaced with a halo group. Examples of haloalkoxy groupsinclude —OCF₃ and —OCHF₂.

A “linker,” as used herein, means a diradical having from 1-6 atoms incontiguous linear connectivity that covalently connects the Y group of acompound of this invention to the pyrazine ring, as illustrated informulas (I) through (VI). The atoms of the linker in contiguous linearconnectivity may be connected by saturated or unsaturated covalentbonds. Linker include, but are not limited to, diradicals of alkyl,alkenyl, alkynyl, heteroalkyl, carbonyl, thiocarbonyl, amide, thioamide,ester, imino, ureido, guanadino, hydrazinyl, and sulfonylamino.

The term “contiguous linear connectivity” means connected together so asto form an uninterrupted linear array or series of atoms. For example, alinker of the compounds described herein having a specified number ofatoms in contiguous linear connectivity has at least that number ofatoms connected together so as to form an uninterrupted chain, but mayalso include additional atoms that are not so connected (e.g., branchesor atoms contained within a ring system).

The terms “bioisostere” and “bioisosteric replacement” have the samemeanings as those generally recognized in the art. Bioisosteres areatoms, ions, or molecules in which the peripheral layers of electronscan be considered substantially identical. The term bioisostere isusually used to mean a portion of an overall molecule, as opposed to theentire molecule itself. Bioisosteric replacement involves using onebioisostere to replace another with the expectation of maintaining orslightly modifying the biological activity of the first bioisostere. Thebioisosteres in this case are thus atoms or groups of atoms havingsimilar size, shape and electron density. Preferred bioisosteres ofesters, amides or carboxylic acids are compounds containing two sitesfor hydrogen bond acceptance. In one embodiment, the ester, amide orcarboxylic acid bioisostere is a 5-membered monocyclic heteroaryl ring,such as an optionally substituted 1H-imidazolyl, an optionallysubstituted oxazolyl, 1H-tetrazolyl, [1,2,4]triazolyl, or an optionallysubstituted[1,2,4]oxadiazolyl.

As used herein, the terms “subject”, “patient” and “animal”, are usedinterchangeably and include, but are not limited to, a cow, monkey,horse, sheep, pig, mini pig, chicken, turkey, quail, cat, dog, mouse,rat, rabbit, guinea pig and human. The preferred subject, patient oranimal is a human.

As used herein, the term “lower” refers to a group having up to fourcarbon atoms. For example, a “lower alkyl” refers to an alkyl radicalhaving from 1 to 4 carbon atoms, and a “lower alkenyl” or “loweralkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4carbon atoms, respectively. A lower alkoxy or a lower alkylsulfanylrefers to an alkoxy or an alkylsulfanyl having from 1 to 4 carbon atoms.Lower substituents are typically preferred.

Where a particular substituent, such as an alkyl substituent, occursmultiple times in a given structure or moeity, the identity of thesubstitutent is independent in each case and may be the same as ordifferent from other occurrences of that substituent in the structure ormoiety. Furthermore, individual substituents in the specific embodimentsand exemplary compounds of this invention are preferred in combinationwith other such substituents in the compounds of this invention, even ifsuch individual substituents are not expressly noted as being preferredor not expressly shown in combination with other substituents.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

Suitable substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino,dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groupsinclude any substituent which will form a stable compound of theinvention. Examples of substituents for an alkyl, alkoxy, alkylsulfanyl,alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkylinclude an alkyl, an alkoxy, an alkylsulfanyl, an alkylamino, adialkylamino, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aheterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteroaralkyl, ahaloalkyl, —C(O)NR₂₃R₂₄, —NR₂₅C(O)R₂₆, halo, —OR₂₅, cyano, nitro,haloalkoxy, —C(O)R₂₅, —NR₂₃R₂₄, —SR₂₅, —C(O)OR₂₅, —OC(O)R₂₅,—NR₂₅C(O)NR₂₃R₂₄, —OC(O)NR₂₃R₂₄, —NR₂₅C(O)OR₂₆, —S(O)_(p)R₂₅, or—S(O)_(p)NR₂₃R₂₄, wherein R₂₃ and R₂₄, for each occurrence are,independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, acycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or aheteraralkyl; or R₂₃ and R₂₄ taken together with the nitrogen to whichthey are attached is a heterocyclyl or a heteroaryl; and R₂₅ and R₂₆ foreach occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl,a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, anaralkyl, or a heteraralkyl.

In one embodiment, examples of suitable substituents for an alkyl,alkoxy, alkylsulfanyl, alkylamino, dialkylamino, alkylene, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl,heteroaryl, and heteroaralkyl groups include a halo, nitro, cyano, ahaloalkyl, —OR₅, —SR₅, —NR₆R₇, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, —C(O)NR₆R₇,—C(O)R₅, —C(O)OR₅, —C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅, —C(S)SR₅,—C(NR₈)NR₆R₇, —C(NR₈)R₅, —C(NR₈)OR₅, —C(NR₈)SR₅, —S(O)_(p)R₅,—S(O)_(p)NR₆R₇, —P(O)(OR₅)₂, —P(S)(OR₅)₂, —P(O)(OR₅)(SR₅),—P(S)(OR₅)(SR₅), —P(O)(SR₅)₂, or —P(S)(SR₅)₂, —OC(O)NR₆R₇, —OC(O)R₅,—OC(O)OR₅, —OC(O)SR₅, —NR₅C(O)NR₆R₇, —NR₅C(O)R₅, —NR₅C(O)OR₅,—NR₅C(O)SR₅, —SC(O)NR₆R₇, —SC(O)R₅, —SC(O)OR₅, —SC(O)SR₅, —OC(S)NR₆R₇,—OC(S)R₅, —OC(S)OR₅, —OC(S)SR₅, —NR₅C(S)NR₆R₇, —NR₅C(S)R₅, —NR₅C(S)OR₅,—NR₅C(S)SR₅, —SC(S)NR₆R₇, —SC(S)R₅, —SC(S)OR₅, —SC(S)SR₅, —OC(NR₈)NR₆R₇,—OC(NR₈)R₅, —OC(NR₈)OR₅, —OC(NR₈)SR₅, —NR₅C(NR₈)NR₆R₇, —NR₅C(NR₈)R₅,—NR₅C(NR₈)OR₅, —NR₅C(NR₈)SR₅, —OS(O)_(p)R₅, —NR₅(O)_(p)R₅, —OP(O)(OR₅)₂,and —OP(S)(OR₅)₂; wherein:

-   -   R₅, for each occurrence, is independently, H, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₆ and R₇, for each occurrence are, independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₆ and R₇ taken together with the nitrogen to which they are        attached are an optionally substituted heterocyclyl or        optionally substituted heteroaryl; and    -   R₈, for each occurrence, is independently —H, a halo, an alkyl,        —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or —C(O)NR₆R₇.

In another embodiment, examples of suitable substituents for an alkyl,alkoxy, alkylsulfanyl, alkylamino, dialkylamino, alkylene, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl,heteroaryl, and heteroaralkyl groups include halogens, lower alkyl,lower haloalkyl, nitro, cyano, —OR, —N(R)₂, —C(O)R, —C(O)OR, —C(O)N(R)₂,—OC(O)R, —NRC(O)R, —OC(O)N(R)₂, —NRC(O)OR, —NRC(NR₈)N(R)₂, —NRC(O)N(R)₂,—S(O)_(p)R, —S(O)_(p)N(R)₂, —NRS(O)_(p)R, or —OP(O)(OR)₂; wherein p is 1or 2.

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and anysaturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, andheteroaralkyl groups, may also be substituted with ═O, ═S, ═N—R₈.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent thenitrogen may be a quaternary nitrogen.

Choices and combinations of substituents and variables envisioned bythis invention are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject). Typically, such compounds arestable at a temperature of 40° C. or less, in the absence of excessivemoisture, for at least one week. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

Unless indicated otherwise, the compounds of the invention containingreactive functional groups (such as, without limitation, carboxy,hydroxy, and amino moieties) also include protected derivatives thereof.“Protected derivatives” are those compounds in which a reactive site orsites are blocked with one or more protecting groups. Suitableprotecting groups for carboxy moieties include benzyl, tert-butyl, andthe like. Suitable protecting groups for amino and amido groups includeacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitableprotecting groups for hydroxy include benzyl, trimethyl silyl (TMS) andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981,the entire teachings of which are incorporated herein by reference.

As used herein, the term “compound(s) of this invention” and similarterms refers to a compound of any one of formulas (I) through (VI), orTable 1, or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof and also include protected derivatives thereof.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may only become active upon suchreaction under biological conditions, but they may have activity intheir unreacted forms. Examples of prodrugs contemplated in thisinvention include, but are not limited to, analogs or derivatives ofcompounds of any one of formulas (I) through (VI), or Table 1 thatcomprise biohydrolyzable moieties such as biohydrolyzable amides,biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, and biohydrolyzable phosphateanalogues. Other examples of prodrugs include derivatives of compoundsof any one of formulas (I) through (VI), or of Table 1 that comprise—NO, —NO₂, —ONO, or —ONO₂ moieties. Prodrugs can typically be preparedusing well-known methods, such as those described by 1 BURGER'SMEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (ManfredE. Wolff ed., 5^(th) ed), the entire teachings of which are incorporatedherein by reference.

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide, or phosphate analogue, respectively, that either: 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as uptake,duration of action, or onset of action; or 2) is itself biologicallyinactive but is converted in vivo to a biologically active compound.Examples of biohydrolyzable amides include, but are not limited to,lower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

As used herein, the term “pharmaceutically acceptable salt,” is a saltformed from an acid and a basic group of one of the compounds of any oneof formulas (I) through (VI) or of Table 1. Illustrative salts include,but are not limited, to sulfate, citrate, acetate, oxalate, chloride,bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from acompound of any one of formulas (I) through (VI) or Table 1 having anacidic functional group, such as a carboxylic acid functional group, anda pharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)-amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)-amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of any one of formulas (I) through (VI) orTable 1 having a basic functional group, such as an amino functionalgroup, and a pharmaceutically acceptable inorganic or organic acid.Suitable acids include, but are not limited to, hydrogen sulfate, citricacid, acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide,hydrogen iodide, nitric acid, phosphoric acid, isonicotinic acid, lacticacid, salicylic acid, tartaric acid, ascorbic acid, succinic acid,maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid,saccharic acid, formic acid, benzoic acid, glutamic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, andp-toluenesulfonic acid.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more solvent molecules toone or more molecules of a compound of any one of formulas (I) through(VI) or Table 1. The term solvate includes hydrates (e.g., hemi-hydrate,mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like).

As used herein, the term “clathrate” means a compound of the presentinvention or a salt thereof in the form of a crystal lattice thatcontains spaces (e.g., channels) that have a guest molecule (e.g., asolvent or water) trapped within.

As used herein, the term “asthma” means a pulmonary disease, disorder orcondition characterized by reversible airway obstruction, airwayinflammation, and increased airway responsiveness to a variety ofstimuli.

“Immunosuppression” refers to impairment of any component of the immunesystem resulting in decreased immune function. This impairment may bemeasured by any conventional means including whole blood assays oflymphocyte function, detection of lymphocyte proliferation andassessment of the expression of T cell surface antigens. The antisheepred blood cell (SRBC) primary (IgM) antibody response assay (usuallyreferred to as the plaque assay) is one specific method. This and othermethods are described in Luster, M. I., Portier, C., Pait, D. G., White,K. L., Jr., Gennings, C., Munson, A. E., and Rosenthal, G. J. (1992).“Risk Assessment in Immunotoxicology I: Sensitivity and Predictabilityof Immune Tests.” Fundam. Appl. Toxicol., 18, 200-210. Measuring theimmune response to a T-cell dependent immunogen is another particularlyuseful assay (Dean, J. H., House, R. V., and Luster, M. I. (2001).“Immunotoxicology: Effects of, and Responses to, Drugs and Chemicals.”In Principles and Methods of Toxicology: Fourth Edition (A. W. Hayes,Ed.), pp. 1415-1450, Taylor & Francis, Philadelphia, Pa.).

The compounds of this invention can be used to treat subjects withimmune disorders. As used herein, the term “immune disorder” and liketerms means a disease, disorder or condition caused by the immune systemof an animal, including autoimmune disorders. Immune disorders includethose diseases, disorders or conditions that have an immune componentand those that are substantially or entirely immune system-mediated.Autoimmune disorders are those wherein the animal's own immune systemmistakenly attacks itself, thereby targeting the cells, tissues, and/ororgans of the animal's own body. For example, the autoimmune reaction isdirected against the nervous system in multiple sclerosis and the gut inCrohn's disease. In other autoimmune disorders such as systemic lupuserythematosus (lupus), affected tissues and organs may vary amongindividuals with the same disease. One person with lupus may haveaffected skin and joints whereas another may have affected skin, kidney,and lungs. Ultimately, damage to certain tissues by the immune systemmay be permanent, as with destruction of insulin-producing cells of thepancreas in Type 1 diabetes mellitus. Specific autoimmune disorders thatmay be ameliorated using the compounds and methods of this inventioninclude without limitation, autoimmune disorders of the nervous system(e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathiessuch as Guillain-Barré, and autoimmune uveitis), autoimmune disorders ofthe blood (e.g., autoimmune hemolytic anemia, pernicious anemia, andautoimmune thrombocytopenia), autoimmune disorders of the blood vessels(e.g., temporal arteritis, anti-phospholipid syndrome, vasculitides suchas Wegener's granulomatosis, and Behcet's disease), autoimmune disordersof the skin (e.g., psoriasis, dermatitis herpetiformis, pemphigusvulgaris, and vitiligo), autoimmune disorders of the gastrointestinalsystem (e.g., Crohn's disease, ulcerative colitis, primary biliarycirrhosis, and autoimmune hepatitis), autoimmune disorders of theendocrine glands (e.g., Type 1 or immune-mediated diabetes mellitus,Grave's disease. Hashimoto's thyroiditis, autoimmune oophoritis andorchitis, and autoimmune disorder of the adrenal gland); and autoimmunedisorders of multiple organs (including connective tissue andmusculoskeletal system diseases) (e.g., rheumatoid arthritis, systemiclupus erythematosus, scleroderma, polymyositis, dermatomyositis,spondyloarthropathies such as ankylosing spondylitis, and Sjogren'ssyndrome). In addition, other immune system mediated diseases, such asgraft-versus-host disease and allergic disorders, are also included inthe definition of immune disorders herein. Because a number of immunedisorders are caused by inflammation, there is some overlap betweendisorders that are considered immune disorders and inflammatorydisorders. For the purpose of this invention, in the case of such anoverlapping disorder, it may be considered either an immune disorder oran inflammatory disorder. “Treatment of an immune disorder” hereinrefers to administering a compound or a composition of the invention toa subject, who has an immune disorder, a symptom of such a disease or apredisposition towards such a disease, with the purpose to cure,relieve, alter, affect, or prevent the autoimmune disorder, the symptomof it, or the predisposition towards it.

As used herein, the term “allergic disorder” means a disease, conditionor disorder associated with an allergic response against normallyinnocuous substances. These substances may be found in the environment(such as indoor air pollutants and aeroallergens) or they may benon-environmental (such as those causing dermatological or foodallergies). Allergens can enter the body through a number of routes,including by inhalation, ingestion, contact with the skin or injection(including by insect sting). Many allergic disorders are linked toatopy, a predisposition to generate the allergic antibody IgE. BecauseIgE is able to sensitize mast cells anywhere in the body, atopicindividuals often express disease in more than one organ. For thepurpose of this invention, allergic disorders include anyhypersensitivity that occurs upon re-exposure to the sensitizingallergen, which in turn causes the release of inflammatory mediators.Allergic disorders include without limitation, allergic rhinitis (e.g.,hay fever), sinusitis, rhinosinusitis, chronic or recurrent otitismedia, drug reactions, insect sting reactions, latex reactions,conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions,atopic dermatitis, asthma and food allergies.

The compounds of this invention can be used to prevent or to treatsubjects with inflammatory disorders. As used herein, an “inflammatorydisorder” means a disease, disorder or condition characterized byinflammation of body tissue or having an inflammatory component. Theseinclude local inflammatory responses and systemic inflammation. Examplesof such inflammatory disorders include: transplant rejection, includingskin graft rejection; chronic inflammatory disorders of the joints,including arthritis, rheumatoid arthritis, osteoarthritis and bonediseases associated with increased bone resorption; inflammatory boweldiseases such as ileitis, ulcerative colitis, Barrett's syndrome, andCrohn's disease; inflammatory lung disorders such as asthma, adultrespiratory distress syndrome, and chronic obstructive airway disease;inflammatory disorders of the eye including corneal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis;chronic inflammatory disorders of the gums, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney including uremic complications, glomerulonephritis and nephrosis;inflammatory disorders of the skin including sclerodermatitis, psoriasisand eczema; inflammatory diseases of the central nervous system,including chronic demyelinating diseases of the nervous system, multiplesclerosis, AIDS-related neurodegeneration and Alzheimer's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis and viral orautoimmune encephalitis; autoimmune disorders, immune-complexvasculitis, systemic lupus and erythematodes; systemic lupuserythematosus (SLE); and inflammatory diseases of the heart such ascardiomyopathy, ischemic heart disease hypercholesterolemia,atherosclerosis; as well as various other diseases with significantinflammatory components, including preeclampsia; chronic liver failure,brain and spinal cord trauma, and cancer. There may also be a systemicinflammation of the body, exemplified by gram-positive or gram negativeshock, hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to pro-inflammatory cytokines, e.g., shockassociated with pro-inflammatory cytokines. Such shock can be induced,e.g., by a chemotherapeutic agent used in cancer chemotherapy.“Treatment of an inflammatory disorder” herein refers to administering acompound or a composition of the invention to a subject, who has aninflammatory disorder, a symptom of such a disorder or a predispositiontowards such a disorder, with the purpose to cure, relieve, alter,affect, or prevent the inflammatory disorder, the symptom of it, or thepredisposition towards it.

An “effective amount” is the quantity of compound in which a beneficialoutcome is achieved when the compound is administered to a subject oralternatively, the quantity of compound that possess a desired activityin-vivo or in-vitro. In the case of inflammatory disorders andautoimmune disorders, a beneficial clinical outcome includes reductionin the extent or severity of the symptoms associated with the disease ordisorder and/or an increase in the longevity and/or quality of life ofthe subject compared with the absence of the treatment. The preciseamount of compound administered to a subject will depend on the type andseverity of the disease or condition and on the characteristics of thesubject, such as general health, age, sex, body weight and tolerance todrugs. It will also depend on the degree, severity and type ofinflammatory disorder, autoimmune disorder, allergic disorder, or thedegree of immunosuppression sought. The skilled artisan will be able todetermine appropriate dosages depending on these and other factors.Effective amounts of the disclosed compounds typically range betweenabout 1 mg/mm² per day and about 10 grams/mm² per day, and preferablybetween 10 mg/mm² per day and about 1 gram/mm².

The compounds of the invention may contain one or more chiral centersand/or double bonds and, therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to this invention, the chemical structuresdepicted herein, including the compounds of this invention, encompassall of the corresponding compounds' enantiomers and stereoisomers, thatis, both the stereomerically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and enantiomeric,diastereomeric, and geometric isomeric mixtures. In some cases, oneenantiomer, diastereomer, or geometric isomer will possess superioractivity or an improved toxicity or kinetic profile compared to others.In those cases, such enantiomers, diastereomers, and geometric isomersof a compound of this invention are preferred.

The term “inhibit production of IL-2” and like terms means inhibitingIL-2 synthesis (e.g. by inhibiting transcription (mRNA expression), ortranslation (protein expression)) and/or inhibiting IL-2 secretion in acell that has the ability to produce and/or secrete IL-2 (e.g., Tlymphocyte). Likewise, the term “inhibiting production of IL-4, IL-5,IL-13, GM-CSF, TNF-α or INF-γ means inhibiting the synthesis (e.g. byinhibiting transcription, or translation) and/or inhibiting thesecretion in a cell that has the ability to produce and/or secrete thesecytokines.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound.

As used herein, a composition that is “substantially free” of a compoundmeans that the composition contains less than about 20% by weight, morepreferably less than about 10% by weight, even more preferably less thanabout 5% by weight, and most preferably less than about 3% by weight ofthe compound.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct, more preferably more than about 90% by weight of the desiredproduct, even more preferably more than about 95% by weight of thedesired product, and most preferably more than about 97% by weight ofthe desired product.

As used herein, a racemic mixture means about 50% of one enantiomer andabout 50% of is corresponding enantiomer relative to all chiral centersin the molecule. The invention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds of any one of formulas(I) through (VI) or Table 1.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

When administered to a patient, e.g., to a non-human animal forveterinary use or for improvement of livestock, or to a human forclinical use, the compounds of the invention are typically administeredin isolated form or as the isolated form in a pharmaceuticalcomposition. As used herein, “isolated” means that the compounds of theinvention are separated from other components of either (a) a naturalsource, such as a plant or cell, preferably bacterial culture, or (b) asynthetic organic chemical reaction mixture. Preferably, viaconventional techniques, the compounds of the invention are purified. Asused herein, “purified” means that when isolated, the isolate containsat least 95%, preferably at least 98%, of a single compound of theinvention by weight of the isolate.

Only those choices and combinations of substituents that result in astable structure are contemplated. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

Specific Embodiments

The invention relates to compounds and pharmaceutical compositions thatare particularly useful for immunosuppression or to treat or preventinflammatory conditions, immune disorders, and allergic disorders.

In some embodiments, the invention relates to compounds represented bystructural formula (I):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁, X₂, and X₃ are, independently, CH, CR₁, or N;    -   L is a linker;    -   Y is an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, or an optionally substituted heteroaryl;    -   each Z is independently selected from the group consisting of a        lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower        alkyl sulfanyl, cyano, nitro, —N(R)₂, —NRC(O)R, —C(O)N(R)₂, or        lower haloalkoxy;    -   R, for each occurrence, is independently, H or a lower alkyl;    -   R₁, for each occurrence, is an independently selected        substituent;    -   R₄ is H or a substituent;    -   m is 0, 1, or 2; and    -   n is 0, 1 or 2.

In some embodiments, the invention relates to compounds represented bystructural formula (II):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   Y, L, Z, and n are defined as for formula (I);    -   R₉ is a lower alkyl, a halo, a lower haloalkyl, a lower alkoxy,        a lower haloalkoxy, —OH, —C(O)OR, —N(R)₂, —C(O)N(R)₂, —OC(O)R,        —NRC(O)R, or an optionally substituted heteroaryl; and    -   R₁₀ a halo, a lower alkyl, a lower haloalkyl, a lower alkoxy, or        a lower alkylsulfanyl.

In some embodiments, the invention relates to compounds represented bystructural formula (III):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   L, Y, Z, R, R₁, R₄, m, and n are defined as for formula (I);    -   ring A is aromatic or non-aromatic; and    -   X₅ is CH, CR₁, or N.

In some embodiments, the invention relates to compounds represented bystructural formula (IV):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   Y, L, Z, and n are defined as for formula (IV); and    -   R₁₀ is defined as for formula (II).

In some embodiments, the invention relates to compounds represented bystructural formula (V):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   Y, L, Z, and n are defined as for formula (IV); and    -   R₁₀ is defined as for formula (II).

In some embodiments, the invention relates to compounds represented bystructural formula (VI):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   Y, L, Z, and n are defined as for formula (IV); and    -   R₁₀ is defined as for formula (II).

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), L is selected from the group consistingof —NRC(R)₂—, —C(R)₂NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—, —C(S)—, —C(NR₈)—,—NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—, —C(NR₈)—NR—, —NRC(O)NR—, —NRC(S)NR—,—NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—, —NRS(O)₂NR—, —NRC(R)₂NR—, —O—, —S—,—NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or —CR═N—NR—;

wherein:

-   -   R₅, for each occurrence, is independently, H, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₆ and R₇, for each occurrence are, independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₆ and R₇ taken together with the nitrogen to which they are        attached are an optionally substituted heterocyclyl or        optionally substituted heteroaryl; and    -   R₈, for each occurrence, is independently —H, a halo, an alkyl,        —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or —C(O)NR₆R₇.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), L is —NRC(R)₂—, —C(R)₂NR—, —NR—C(O)—,or —C(O)—NR—.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), L is —NH—C(O)— or —C(O)—NH—.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), L is —NH—CH₂— or —CH₂—NH—.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), Y is an optionally substituted aryl oran optionally substituted heteroaryl.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), Y is selected from the group consistingof an optionally substituted phenyl, an optionally substituted naphthyl,an optionally substituted pyridyl, an optionally substituted furyl, anoptionally substituted thienyl, an optionally substituted pyrrolyl, anoptionally substituted oxazolyl, an optionally substituted imidazolyl,an optionally substituted indolizinyl, an optionally substitutedthiazolyl, an optionally substituted isoxazolyl, an optionallysubstituted pyrazolyl, an optionally substituted isothiazolyl, anoptionally substituted pyridazinyl, an optionally substitutedpyrimidinyl, an optionally substituted pyrazinyl, an optionallysubstituted triazinyl, an optionally substituted triazolyl, anoptionally substituted thiadiazolyl, an optionally substitutedpyrazinyl, an optionally substituted quinolinyl, an optionallysubstituted isoquinolinyl, an optionally substituted indazolyl, anoptionally substituted benzoxazolyl, an optionally substitutedbenzofuryl, an optionally substituted benzothiazolyl, an optionallysubstituted indolizinyl, an optionally substituted imidazopyridinyl, anoptionally substituted isothiazolyl, an optionally substitutedtetrazolyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzothiazolyl, an optionally substituted benzothiadiazolyl,an optionally substituted benzoxadiazolyl, an optionally substitutedindolyl, an optionally substituted tetrahydroindolyl, an optionallysubstituted azaindolyl, an optionally substituted imidazopyridyl, anoptionally substituted quinazolinyl, an optionally substituted purinyl,an optionally substituted pyrrolo[2,3]pyrimidyl, an optionallysubstituted pyridopyrimidyl, an optionally substitutedpyrazolo[3,4]pyrimidyl or an optionally substituted benzo(b)thienyl.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), Y is an optionally substituted phenyl,an optionally substituted pyridinyl, or an optionally substituted[,1,2,3]thiadiazolyl.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), Y is optionally substituted with one ormore substituents selected from the group consisting of halo, loweralkyl, lower haloalkyl, nitro, cyano, —OR, —N(R)₂, —C(O)R, —C(O)OR,—C(O)N(R)₂, —OC(O)R, —NRC(O)R, —OC(O)N(R)₂, —NRC(O)OR, —NRC(NR₈)N(R)₂,—NRC(O)N(R)₂, —S(O)_(p)R, —S(O)_(p)N(R)₂, —NRS(O)_(p)R, or —OP(O)(OR)₂;wherein p is 1 or 2.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), Y is selected from the group consistingof:

-   -   wherein:    -   X₄ is CH or N;    -   R₂ is H, a halo, a lower alkyl, a lower haloalkyl, a lower        alkoxy, or a lower haloalkoxy;    -   R₃ is a halo, a lower alkyl, a lower haloalkyl, a lower alkoxy,        or a lower haloalkoxy.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), Y is an optionally substituted alkyl oran optionally substituted cycloalkyl.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), Y is selected from the group consistingof methyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl,isopentyl, 2-methyl-butyl, n-hexyl, 2-methyl-pentyl, 3-methyl-pentyl,4-methyl-pentyl, 2-ethyl-butyl, 3-ethyl-butyl, cyclooctyl, cycloheptyl,cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, each of which can beoptionally substituted with one or more substituent selected from thegroup consisting of a halo, lower alkyl, lower haloalkyl, nitro, cyano,—OR, —SR, pentyl, —N(R)₂, —C(O)R, —C(O)OR, —C(O)N(R)₂, —OC(O)R,—NRC(O)R, —OC(O)N(R)₂, —NRC(O)OR, —OC(O)OR, —NRC(NR₈)N(R)₂,—NRC(O)N(R)₂, —S(O)_(p)R, —S(O)_(p)N(R)₂, —NRS(O)_(p)R, or —OP(O)(OR)₂;wherein p is 1 or 2.

In some embodiments of the compounds represented by formula (I), (II),(III), (IV), (V), or (VI), Y is an optionally substituted cycloalkyl.For example, Y is an optionally substituted cyclohexyl or an optionallysubstituted cyclopentyl.

In some embodiments of the compounds represented by formula (I), (II),(III), (IV), (V), or (VI), Y is an optionally substituted alkyl. Forexample, Y is an optionally substituted methyl or ethyl, or anoptionally substituted, branched or unbranched propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl. Preferably, Y is an unsubstitutedmethyl or ethyl, or an unsubstituted, branched or unbranched propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl.

In some one embodiments of the compounds represented by formula (I) or(III), R₁, for each occurrence, is independently, selected from thegroup consisting of a halo, nitro, cyano, a haloalkyl, —OR₅, —SR₅,—NR₆R₇, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, —C(O)NR₆R₇, —C(O)R₅, —C(O)OR₅, —C(O)SR₅,—C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅, —C(S)SR₅, —C(NR₈)NR₆R₇, —C(NR₈)R₅,—C(NR₈)OR₅, —C(NR₈)SR₅, —S(O)_(p)R₅, —S(O)_(p)NR₆R₇, —P(O)(OR₅)₂,—P(S)(OR₅)₂, —P(O)(OR₅)(SR₅), —P(S)(OR₅)(SR₅), —P(O)(SR₅)₂, or—P(S)(SR₅)₂, —OC(O)NR₆R₇, —OC(O)R₅, —OC(O)OR₅, —OC(O)SR₅, —NR₅C(O)NR₆R₇,—NR₅C(O)R₅, —NR₅C(O)OR₅, —NR₅C(O)SR₅, —SC(O)NR₆R₇, —SC(O)R₅, —SC(O)OR₅,—SC(O)SR₅, —OC(S)NR₆R₇, —OC(S)R₅, —OC(S)OR₅, —OC(S)SR₅, —NR₅C(S)NR₆R₇,—NR₅C(S)R₅, —NR₅C(S)OR₅, —NR₅C(S)SR₅, —SC(S)NR₆R₇, —SC(S)R₅, —SC(S)OR₅,—SC(S)SR₅, —OC(NR₈)NR₆R₇, —OC(NR₈)R₅, —OC(NR₈)OR₅, —OC(NR₈)SR₅,—NR₅C(NR₈)NR₆R₇, —NR₅C(NR₈)R₅, —NR₅C(NR₈)OR₅, —NR₅C(NR₈)SR₅,—OS(O)_(p)R₅, —NR₅S(O)_(p)R₅, —OP(O)(OR₅)₂, and —OP(S)(OR₅)₂; and

-   -   R₄ is H, a halo, nitro, cyano, a haloalkyl, —OR₅, —SR₅, —NR₆R₇,        an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted aralkyl, an optionally substituted        heteraralkyl, —C(O)NR₆R₇, —C(O)R₅, —C(O)OR₅, —C(O)SR₅,        —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅, —C(S)SR₅, —C(NR₈)NR₆R₇,        —C(NR₈)R₅, —C(NR₈)OR₅, —C(NR₈)SR₅, —S(O)_(p)R₅, —S(O)_(p)NR₆R₇,        —P(O)(OR₅)₂, —P(S)(OR₅)₂, —P(O)(OR₅)(SR₅), —P(S)(OR₅)(SR₅),        —P(O)(SR₅)₂, or —P(S)(SR₅)₂, —OC(O)NR₆R₇, —OC(O)R₅, —OC(O)OR₅,        —OC(O)SR₅, —NR₅C(O)NR₆R₇, —NR₅C(O)R₅, —NR₅C(O)OR₅, —NR₅C(O)SR₅,        —SC(O)NR₆R₇, —SC(O)R₅, —SC(O)OR₅, —SC(O)SR₅, —OC(S)NR₆R₇,        —OC(S)R₅, —OC(S)OR₅, —OC(S)SR₅, —NR₅C(S)NR₆R₇, —NR₅C(S)R₅,        —NR₅C(S)OR₅, —NR₅C(S)SR₅, —SC(S)NR₆R₇, —SC(S)R₅, —SC(S)OR₅,        —SC(S)SR₅, —OC(NR₈)NR₆R₇, —OC(NR₈)R₅, —OC(NR₈)OR₅, —OC(NR₈)SR₅,        —NR₅C(NR₈)NR₆R₇, —NR₅C(NR₈)R₅, —NR₅C(NR₈)OR₅, —NR₅C(NR₈)SR₅,        —OS(O)_(p)R₅, —NR₅S(O)_(p)R₅, —OP(O)(OR₅)₂, or —OP(S)(OR₅)₂.

In some one embodiments of the compounds represented by formula (I), X₁and X₂ are CH or CR₁; and X₃ is N. In one aspect of this embodiment, Yis an optionally substituted aryl or an optionally substitutedheteroaryl. In another aspect of this embodiment, Y is an optionallysubstituted alkyl or an optionally substituted cycloalkyl.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), n is 0.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), n is 1. In one aspect of thisembodiment, Z is a halo.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), n is 2. In one aspect of thisembodiment, Z, for each occurrence, is independently, a halo.

In some one embodiments of the compounds represented by formula (I),(II), (III), (IV), (V), or (VI), R is H.

In some embodiments of the compounds represented by formula (I), (II),(III), (IV), (V), or (VI), R, for each occurrence, is independently, alower alkyl, such as methyl.

In some embodiments of the compounds represented by formula (I) or(III), m is 0.

In some embodiments of the compounds represented by formula (I) or(III), m is 1.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   2,6-Difluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide-   3,5-Difluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-isonicotinamide-   3-Fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-isonicotinamide-   N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl-isonicotinamide-   2-Fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide-   2,5-Difluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide-   2,4-Difluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide-   2,3,6-Trifluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide-   4-Chloro-2-fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide-   N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-benzamide-   N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-nicotinamide-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amide-   N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2,6-difluoro-benzamide-   N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide-   N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-fluoro-isonicotinamide-   N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl-isonicotinamide-   N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-fluoro-benzamide-   N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2,5-difluoro-benzamide-   N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2,4-difluoro-benzamide-   N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2,3,6-trifluoro-benzamide-   4-Chloro-N-[5-(5-ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-fluoro-benzamide-   N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-benzamide-   N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-nicotinamide-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(5-ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amide-   1-[5-(2,6-Difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-{5-[(3,5-Difluoro-pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-{5-[(3-Fluoro-pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-{5-[(3-Methyl-pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-[5-(2-Fluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-[5-(2,5-Difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-[5-(2,4-Difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-[5-(2,3,6-Trifluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-[5-(4-Chloro-2-fluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-[5-(2-Methyl-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-{5-[(2-Methyl-pyridine-3-carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-{5-[(4-Methyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   (2,6-Difluoro-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   (3,5-Difluoro-pyridin-4-ylmethyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   (3-Fluoro-pyridin-4-ylmethyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(3-methyl-pyridin-4-ylmethyl)-amine-   (2-Fluoro-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   (2,5-Difluoro-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   (2,4-Difluoro-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2,3,6-trifluoro-benzyl)-amine-   (4-Chloro-2-fluoro-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-benzyl)-amine-   [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-pyridin-3-ylmethyl)-amine-   [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(4-methyl-[1,2,3]thiadiazol-5-ylmethyl)-amine-   1-[5-(2,6-Difluoro-benzylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-{5-[(3,5-Difluoro-pyridin-4-ylmethyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-{5-[(3-Fluoro-pyridin-4-ylmethyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-{5-[(3-Methyl-pyridin-4-ylmethyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-[5-(2-Fluoro-benzylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-[5-(2,5-Difluoro-benzylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-[5-(2,4-Difluoro-benzylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-[5-(2,3,6-Trifluoro-benzylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-[5-(4-Chloro-2-fluoro-benzylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-[5-(2-Methyl-benzylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-{5-[(2-Methyl-pyridin-3-ylmethyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   1-{5-[(4-Methyl-[1,2,3]thiadiazol-5-ylmethyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic    acid methyl ester-   Cyclohexanecarboxylic acid    [5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amide-   Cyclopentanecarboxylic acid    [5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amide-   Cyclobutanecarboxylic acid    [5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amide-   Cyclopropanecarboxylic acid    [5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amide-   N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-butyramide-   Pentanoic acid    [5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amide-   N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-butyramide-   N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-propionamide-   2,6-Difluoro-N-[5-(6-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide-   N-[5-(6-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl-isonicotinamide-   N-[5-(6-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-nicotinamide-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(6-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amide-   Cyclohexylmethyl-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   Cyclopentylmethyl-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   Cyclobutylmethyl-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   Cyclopropylmethyl-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   Butyl-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-pentyl-amine-   [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-butyl)-amine-   [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-propyl-amine-   (2,6-Difluoro-benzyl)-[5-(6-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine-   [5-(6-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(3-methyl-pyridin-4-ylmethyl)-amine-   [5-(6-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-pyridin-3-ylmethyl)-amine    -   pharmaceutically acceptable salts, solvates, clathrates, or        prodrugs thereof.

All of the features, specific embodiments and particular substituentsdisclosed herein may be combined in any combination. Each feature,embodiment or substituent disclosed in this specification may bereplaced by an alternative feature, embodiment or substituent servingthe same, equivalent, or similar purpose. In the case of chemicalcompounds, specific values for variables (e.g., values shown in theexemplary compounds disclosed herein) in any chemical formula disclosedherein can be combined in any combination resulting in a stablestructure. Furthermore, specific values (whether preferred or not) forsubstituents in one type of chemical structure may be combined withvalues for other substituents (whether preferred or not) in the same ordifferent type of chemical structure. Thus, unless expressly statedotherwise, each feature, embodiment or substituent disclosed is only anexample of a generic series of equivalent or similar features,embodiments or substituents.

In another embodiment, the invention relates to pharmaceuticalcompositions that comprise a compound of any one of formulas (I) through(VI), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, as an active ingredient, and apharmaceutically acceptable carrier or vehicle. The compositions areuseful for immunosuppression or to treat or prevent inflammatoryconditions, allergic conditions or immune disorders.

In another embodiment, the invention relates to methods forimmunosuppression or for treating or preventing inflammatory conditions,immune disorders, or allergic disorders in a patient in need thereofcomprising administering an effective amount of a compound representedby any one of formulas (I) through (VI), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, the invention relates to methods forimmunosuppression or for treating or preventing inflammatory conditions,immune disorders, or allergic disorders in a patient in need thereofcomprising administering an effective amount of a pharmaceuticalcomposition that comprises a compound represented by any one of formulas(I) through (VI), or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof.

In another embodiment, compounds of any one of formulas (I) through(VI), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, are particularly useful inhibiting immunecell (e.g., T-cells and/or B-cells) activation (e.g., activation inresponse to an antigen) and/or T cell and/or B cell proliferation.Indicators of immune cell activation include secretion of IL-2 by Tcells, proliferation of T cells and/or B cells, and the like. In oneembodiment, immune cell activation and/or T cell and/or B cellproliferation is inhibited in a mammal (e.g., a human), by administeringto the mammal (e.g., human) a compound of any one of formulas (I)through (VI) or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof.

In another embodiment, compounds of any one of formula (I) through (VI),or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate,or prodrug thereof, can inhibit the production of certain cytokines thatregulate immune cell activation. For example, compounds of any one offormulas (I) through (VI), or Table 1, or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, can inhibit the productionof IL-2, IL-4, IL-5, IL-13, GM-CSF, IFN-γ, TNF-α and combinationsthereof. In one embodiment, cytokine production is inhibited in a mammal(e.g., a human), by administering to the mammal (e.g., human) a compoundof any one of formulas (I) through (VI) or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, compounds of any one of formulas (I) through(VI), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, can modulate the activity of one or moreion channel, such as CRAC ion channels, involved in activation of immunecells. In one embodiment, a compound of any one of formulas (I) through(VI) or Table 1 can inhibit the influx of calcium ions into an immunecell (e.g., T cells, B cells, and/or mast cells) by inhibiting theaction of CRAC ion channels either directly or indirectly. In general, adecrease in I_(CRAC) current upon contacting a cell with a compound isone indicator that the compound inhibitions CRAC ion channels. I_(CRAC)current can be measured, for example, using a patch clamp technique,which is described in more detail in the examples below. In oneembodiment, a compound of any one of formulas (I) through (VI) or Table1 modulates an ion channel in a mammal (e.g., a human). In anotherembodiment, the activity of one or more ion channels is inhibited in amammal (e.g., a human), by administering to the mammal (e.g., human) acompound of any one of formulas (I) through (VI) or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, compounds of any one of formula (I) through (VI),or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate,or prodrug thereof, can inhibit degranulation of mast cell. Inhibitionof mast cell degranulation can determined as described in theexperimental section herein or by any method known to those skilled inthe art. In one embodiment, mast cell degranulation is inhibited in amammal (e.g., a human), by administering to the mammal (e.g., human) acompound of any one of formulas (I) through (VI) or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

Exemplary Compounds of the Invention

Exemplary compounds of the invention are depicted in Table 1 below.

TABLE 1 Compound No. Structure Chemical Name 1

2,6-Difluoro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 2

3,5-Difluoro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-isonicotinamide 3

3-Fluoro-N-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-isonicotinamide 4

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl- isonicotinamide 5

2-Fluoro-N-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 6

2,5-Difluoro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 7

2,4-Difluoro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 8

2,3,6-Trifluoro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 9

4-Chloro-2-fluoro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 10

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-benzamide 11

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-nicotinamide 12

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(5-methoxy-2-trifluoromethyl- benzoimidazol-1-yl)-pyrazin- 2-yl]-amide 13

N-[5-(5-Ethoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2,6-difluoro-benzamide 14

N-[5-(5-Ethoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-3,5-difluoro- isonicotinamide 15

N-[5-(5-Ethoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-3-fluoro-isonicotinamide 16

N-[5-(5-Ethoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl- isonicotinamide 17

N-[5-(5-Ethoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2-fluoro-benzamide 18

N-[5-(5-Ethoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2,5-difluoro-benzamide 19

N-[5-(5-Ethoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2,4-difluoro-benzamide 20

N-[5-(5-Ethoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2,3,6-trifluoro- benzamide 21

4-Chloro-N-[5-(5-ethoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2-fluoro-benzamide 22

N-[5-(5-Ethoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-benzamide 23

N-[5-(5-Ethoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-nicotinamide 24

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(5-ethoxy-2-trifluoromethyl- benzoimidazol-1-yl)-pyrazin- 2-yl]-amide 25

1-[5-(2,6-Difluoro- benzoylamino)-pyrazin-2-yl]- 2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 26

1-{5-[(3,5-Difluoro-pyridine-4- carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H- benzoimidazole-5-carboxylic acid methyl ester27

1-{5-[(3-Fluoro-pyridine-4- carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H- benzoimidazole-5-carboxylic acid methyl ester28

1-{5-[(3-Methyl-pyridine-4- carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H- benzoimidazole-5-carboxylic acid methyl ester29

1-[5-(2-Fluoro- benzoylamino)-pyrazin-2-yl]- 2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 30

1-[5-(2,5-Difluoro- benzoylamino)-pyrazin-2-yl]- 2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 31

1-[5-(2,4-Difluoro- benzoylamino)-pyrazin-2-yl]- 2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 32

1-[5-(2,3,6-Trifluoro- benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H- benzoimidazole-5-carboxylic acid methyl ester 33

1-[5-(4-Chloro-2-fluoro- benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H- benzoimidazole-5-carboxylic acid methyl ester 34

1-[5-(2-Methyl- benzoylamino)-pyrazin-2-yl]- 2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 35

1-{5-[(2-Methyl-pyridine-3- carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H- benzoimidazole-5-carboxylic acid methyl ester36

1-{5-[(4-Methyl- [1,2,3]thiadiazole-5- carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H- benzoimidazole-5-carboxylic acid methyl ester37

(2,6-Difluoro-benzyl)-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 38

(3,5-Difluoro-pyridin-4- ylmethyl)-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 39

(3-Fluoro-pyridin-4-ylmethyl)- [5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 40

[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-(3-methyl-pyridin-4- ylmethyl)-amine 41

(2-Fluoro-benzyl)-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 42

(2,5-Difluoro-benzyl)-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 43

(2,4-Difluoro-benzyl)-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 44

[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-(2,3,6-trifluoro-benzyl)- amine 45

(4-Chloro-2-fluoro-benzyl)-[5- (5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 46

[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-benzyl)- amine 47

[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-pyridin-3- ylmethyl)-amine 48

[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-(4-methyl- [1,2,3]thiadiazol-5-yl methyl)- amine 49

1-[5-(2,6-Difluoro- benzylamino)-pyrazin-2-yl]-2- trifluoromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 50

1-{5-[(3,5-Difluoro-pyridin-4- methyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H- benzoimidazole-5-carboxylic acid methyl ester51

1-{5-[(3-Fluoro-pyridin-4- ylmethyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H- benzoimidazole-5-carboxylic acid methyl ester52

1-{5-[(3-Methyl-pyridin-4- ylmethyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H- benzoimidazole-5-carboxylic acid methyl ester53

1-[5-(2-Fluoro-benzylamino)- pyrazin-2-yl]-2- trifluoromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 54

1-[5-(2,5-Difluoro- benzylamino)-pyrazin-2-yl]-2- trifluoromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 55

1-[5-(2,4-Difluoro- benzylamino)-pyrazin-2-yl]-2- trifluoromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 56

1-[5-(2,3,6-Trifluoro- benzylamino)-pyrazin-2-yl]-2- trifluoromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 57

1-[5-(4-Chloro-2-fluoro- benzylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H- benzoimidazole-5-carboxylic acid methyl ester 58

1-[5-(2-Methyl-benzylamino)- pyrazin-2-yl]-2- trifluoromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 59

1-{5-[(2-Methyl-pyridin-3- ylmethyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H- benzoimidazole-5-carboxylic acid methyl ester60

1-{5-[(4-Methyl- [1,2,3]thiadiazoi-5-ylmethyl)- amino]-pyrazin-2-yl}-2-trifluoro methyl-1H- benzoimidazole-5-carboxylic acid methyl ester 61

Cyclohexanecarboxylic acid [5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amide 62

Cyclopentanecarboxylic acid [5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amide 63

Cyclobutanecarboxylic acid [5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amide 64

Cyctopropanecarboxylic acid (5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amide 65

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-butyramide 66

Pentanoic acid [5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amide 67

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-butyramide 68

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-propionamide 69

2,6-Difluoro-N-[5-(6- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 70

N-[5-(6-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl- isonicotinamide 71

N-[5-(6-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-nicotinamide 72

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(6-methoxy-2-trifluoromethyl- benzoimidazol-1-yl)-pyrazin- 2-yl]-amide 73

Cyclohexylmethyl-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 74

Cyclopentylmethyl-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 75

Cyclobutylmethyl-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 76

Cyclopropylmethyl-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 77

Butyl-[5-(5-methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-amine 78

(5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-pentyl-amine 79

[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-butyl)-amine 80

[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-propyl-amine 81

(2,6-Difluoro-benzyl)-[5-(6- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 82

[5-(6-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-(3-methyl-pyridin-4- ylmethyl)-amine 83

[5-(6-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-pyridin-3- ylmethyl)-amine 84

[5-(6-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-(4-methyl- [1,2,3]thiadiazol-5-ylmethyl)- amine 85

2-Bromo-N-[5-(5-methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide 86

4-Fluoro-N-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 87

(2-Chloro-benzyl)-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 88

3-Fluoro-N-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 89

(4-Fluoro-benzyl)-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 90

(4-Methoxy-benzyl)-[5-(5- methoxy-2-trifiuoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 91

4-Chloro-N-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 92

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2,3-dimethyl-benzamide 93

4-Cyano-N-[5-(5-methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide 94

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2,4-dimethyl-benzamide 95

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-3-methylsulfanyl- benzamide 96

3-Chloro-N-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 97

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-4-nitro-benzamide 98

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-3-nitro-benzamide 99

2-Chloro-N-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 100

(2-Chloro-6-fluoro-benzyl)-[5- (5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 101

3-Cyano-N-[5-(5-methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide 102

(2-Methoxy-benzyl)-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 103

(3-Methoxy-benzyl)-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-amine 104

3-Methoxy-N-[5-(5-methoxy- 2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 105

[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-pyridin-4-ylmethyl- amine 106

4-Ethyl-N-[5-(5-methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide 107

4-Bromo-N-[5-(5-methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide 108

3-Bromo-N-[5-(5-methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide 109

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-4-propyl-benzamide 110

2,4-Dichloro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 111

2-Methoxy-N-[5-(5-methoxy- 2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 112

3-Iodo-N-[5-(5-methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide 113

2,3-Dichloro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 114

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-isophthalamic acid ethyl ester 115

Benzyl-[5-(5-methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-amine 116

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl-benzamide 117

4-Butyl-N-[5-(5-methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide 118

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-4-methyl-benzamide 119

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-4-methylsulfanyl- benzamide 120

4-Methoxy-N-[5-(5-methoxy- 2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 121

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-3,5-dimethyl-benzamide 122

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2,5-dimethyl-benzamide 123

2-Ethoxy-N-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 124

2,4-Dimethoxy-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 125

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-3-trifluoromethyl- benzamide 126

3,4-Dimethoxy-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 127

2-Fluoro-4-methoxy-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 128

2,3-Dimethoxy-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 129

3,5-Dimethoxy-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 130

5-Bromo-2-fluoro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 131

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-4-pentyl-benzamide 132

4-tert-Butyl-N-[5-(5-methoxy- 2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 133

4-Ethoxy-N-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 134

4-Chloro-2-methoxy-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 135

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-3-nitro- benzamide 136

2,4,5-Trimethoxy-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 137

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-4-trifluoromethyl- benzamide 138

2-Bromo-4-fluoro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 139

4-Chloro-N-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-3-nitro-benzamide 140

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-4-methyl-3-nitro- benzamide 141

4-Isopropyl-N-[5-(5-methoxy- 2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 142

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl-2-nitro- benzamide 143

2,4,5-Trifluoro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 144

2-Methoxy-N-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-4- trifluoromethyl-benzamide 145

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2-trifluoromethyl- benzamide 146

N-[5-(5-Methoxy-2- trifluoromethyl- benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-5-nitro- benzamide 147

3-Methoxy-N-[5-(5-methoxy- 2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-4-nitro-benzamide 148

5-Chloro-2-fluoro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 149

2,3,4-Trifluoro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 150

2-Fluoro-N-[5-(5-methoxy-2- trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-4-nitro-benzamide 151

2-Chloro-5-fluoro-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 152

5-Chloro-2-methoxy-N-[5-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamide 153

2,6-Difluoro-N-[5-(5-oxazol- 2-yl-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin- 2-yl]-benzamideMechanism of Action

Activation of T-lymphocytes in response to an antigen is dependent oncalcium ion oscillations. Calcium ion oscillations in T-lymphocytes aretriggered through stimulation of the T-cell antigen receptor, andinvolve calcium ion influx through the stored-operatedCa²⁺-release-activated Ca²⁺ (CRAC) channel. In addition, antigen induceddegranulation of mast cells has also been shown to be initiated bycalcium ion in flux. Although the molecular structure of the CRAC ionchannel has not been identified, a detailed electrophysiological profileof the channel exist. Thus, modulation (e.g., inhibition) of CRAC ionchannels can be measured by measuring modulation (e.g., inhibition) ofthe I_(CRAC) current. Calcium ion oscillations in T-cells have beenimplicated in the activation of several transcription factors (e.g.,NFAT, Oct/Oap and NFκB) which are critical for T-cell activation (Lewis,Biochemical Society Transactions (2003), 31:925-929, the entireteachings of which are incorporated herein by reference). Withoutwishing to be bound by any theory, it is believed that because thecompounds of the invention inhibit the activity of CRAC ion channels,they inhibit immune cell activation.

Methods of Treatment and Prevention

In accordance with the invention, an effective amount of a compound ofany one of formulas (I) through (VI) or Table 1, or a pharmaceuticallyacceptable salt, solvate, clathrate, and prodrug thereof, or apharmaceutical composition comprising a compound of any one of formulas(I) through (VI) or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, and prodrug thereof, is administered to a patient inneed of immunosuppression or in need of treatment or prevention of aninflammatory condition, an immune disorder, or an allergic disorder.Such patients may be treatment naïve or may experience partial or noresponse to conventional therapies.

Responsiveness to immunosuppression or of a particular inflammatorycondition, immune disorder, or allergic disorder in a subject can bemeasured directly (e.g., measuring blood levels of inflammatorycytokines (such as IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, IFN-γ and thelike) after administration of a compound of this invention), or can beinferred based on an understanding of disease etiology and progression.The compounds of any one of formulas (I) through (VI), or Table 1, orpharmaceutically acceptable salts, solvates, clathrates, and prodrugsthereof can be assayed in vitro or in vivo, for the desired therapeuticor prophylactic activity, prior to use in humans. For example, knownanimal models of inflammatory conditions, immune disorders, or allergicdisorders can be used to demonstrate the safety and efficacy ofcompounds of this invention.

Preparation of Compounds of the Invention

A. Preparation of Benzoimidazolyl Pyrazines (Method I)

The amine group of compound a is protected by treating it with an acidchloride, such as acetyl chloride, in the presence of a base, such astriethylamine, to form compound b. Typically, the reaction is carriedout in an aprotic solvent.

The aromatic ring of compound b is substituted with a nitro group byforming a solution of compound b dissolved in acetic acid and treatingit with nitric acid and heat to form compound c.

The amine protecting group is removed form compound c by heating it withan aqueous solution of potassium hydroxide to form compound d.

An aromatic substitution reaction is carried out by combining a2-halo-5-nitro-pyrazine (compound e) with compound d in dimethylsulfoxide (DMSO) in the presence of a strong base, such as potassiumt-butoxide (t-BuOK), and heated to about 60° C. to form compound f.

Compound f is hydrogenated by dissolving it in ethanol and treating itwith hydrogen gas in the presence of palladium on carbon to reduce thetwo nitro groups to amine groups forming compound g.

The benzoimidazole ring (or purine or imidazopyridine ring) is formed bydissolving compound g in trifluoroacetic acid (TFA) and addingtrifluoroacetic anhydride (TFAA) to form compound h, wherein R₁₁ is CF₃.Typically, the reaction is heated to about 80° C. Alternatively,compound g is dissolved in acetic acid and acetic anhydride is added toform compound h, wherein R₁₁ is CH₃.

Compound h is then treated with a base, such as potassium carbonate, inand alcohol, such as methanol, to form the free amine compound (Compoundi) which can be used to form a number of linkers through which thearomatic and non-aromatic Y-groups can be attached (see below).

B. Preparation of Benzoimidazolyl Pyrazines (Method II)

Scheme II

An aromatic substitution reaction is carried out by combining anaromatic halide (compound j) with 2,5-diaminopyrazine (compound d) in asolvent in the presence of a base to form compound m. The nitro group ofcompound m is reduced to an amine group by catalytic hydrogenation usinga palladium on carbon catalyst to form compound g. Compound g can beconverted to compound i as described above in Scheme I.

C. General Procedure for Amide Coupling Reaction (Method I)

Amine derivative (Compound i) (19.2 mmol) is dissolved in methylenechloride and cooled to 0° C. Pyridine (3.87 ml, 48 mmol) is added to thereaction mixture followed by an acyl chloride (Compound n) (19.2 mmol).This mixture is allowed to warm to room temperature for 35 minutes atwhich time water is added and the reaction mixture is partitionedbetween the methylene chloride and water layers. The organic layer iscollected and dried over a drying agent such as NaSO₄, thenconcentrated. The product is purified using flash chromatography to givea compound of the invention (Compound o) (see Scheme III).

D. General Procedure for Amide Coupling Reaction (Method II)

Amine derivative (Compound q) (19.2 mmol) is dissolved in methylenechloride and cooled to 0° C. Pyridine (3.87 ml, 48 mmol) is added to thereaction mixture followed by a 5-amino-pyrazine-2-carbonyl chloride inwhich the amine group is protected (Compound p) (19.2 mmol). Thismixture is allowed to warm to room temperature for 35 minutes at whichtime water is added and the reaction mixture is partitioned between themethylene chloride and water layers. The organic layer is collected anddried over a drying agent such as NaSO₄, then concentrated. The productis purified using flash chromatography to give Compound r (see SchemeIV). The amine group of Compound r can then be deprotected and convertedto a benzoimidazolyl, purinyl, or imidazopyridinyl group as described inScheme II.

E. Other Linkers

Compounds of the invention in which L is —NHC(S)— or —C(S)NH— can beprepared by treating compounds having an amide linker with Lawesson'sreagent.

Compounds of the invention having —CH₂—NH— or —NH—CH₂— linkers can beprepared by contacting compounds having —NHC(S)— or —C(S)NH— linkerswith Raney Ni. Alternatively, compounds of the invention having a—CH₂—NH— or —NH—CH₂— linker can be prepared by reducing a compoundhaving a —C(O)—NH— or —NH—C(O)— linker, respectively, with, for example,sodium borohydride (see U.S. patent application Ser. No. 10/897,681,filed on Jul. 22, 2004, the entire teachings of which are incorporatedherein by reference). Compounds of the invention having —NH—CH₂— linkercan also be prepared by reacting an amine derivative (Compound i) withan aldehyde (Compound v). Typically, this reaction is carried out underconditions where water is removed from the reaction to form the imine(Compound w). The imine is then treated with sodium borohydride to acompound of the invention that has a —NH—CH₂— linker (see Scheme V).

Compounds of the invention having —C(O)— linkers (Compound dd) can beprepared by a Friedel-Craft acylation reaction by reacting anamino-pyrazine (Compound y), in which the amine group is protected, withan acid chloride (Compound z) in the presence of AlCl₃ to form Compoundaa (see Scheme VI). The amine group of Compound aa can then bedeprotected and converted to a benzoimidazolyl, purinyl, orimidazopyridinyl group as described in Scheme II.

Compounds of the invention that have —C(S)— linkers can be prepared fromcompounds that have carbonyl linkers by treating them with Lawesson'sreagent or P₂S₅ in pyridine.

Compounds of the invention that have a sulfonamide linker (Compound ff)can be prepared by reacting an amine derivative (Compound i) with asulfonyl chloride derivative (Compound ee) as shown in Scheme VII.Typically, the amine derivative (Compound i) is dissolved in a polarsolvent, such as an alcohol, and the sulfonyl chloride derivative(Compound ee) is added. The reaction is typically heated to about 50° C.to about 100° C.

Compounds of the invention having a urea linker (Compound hh) can beprepared by reacting amine derivative (Compound i) with an isocyanate(Compound gg) as shown in Scheme VIII. Typically, the amine derivative(Compound i) is dissolved in a non-polar, aprotic solvent such asdichloromethane (DCM) to which the isocyanate (Compound gg) is added atroom temperature. The reaction is typically stirred for about 5 minutesto about 1 hour to give a compound of the invention having a urea linker(Compound hh).

Compounds of the invention having a thiourea linker (—NHC(S)NH—) can beprepared by treating compounds having a urea linker with Lawesson'sreagent.

Compounds of the invention having a hydrazinyl linker (—NH—N═CH—)(Compound kk) can be prepared by adding an aqueous solution of NaNO₂ (1eq.) to a solution of amine derivative (Compound i) (1 eq.) inconcentrated HCl at about 0° C. After the solution is stirred at about0° C. for about 15 minute to about 1 hour, 2.4 eq. of SnCl₂ inconcentrated HCl is added, and the reaction is stirred at about 0° C.for about 1 hour to give a hydrazinium chloride intermediate (CompoundII). The hydrazinium chloride intermediate (Compound II) is dissolved inacetic acid and an alcohol, such as methanol, and an aldehyde (Compoundjj) is added. The reaction is stirred at room temperature for about anhour to give a compound of the invention having a hydrazinyl linker(Compound kk) (see Scheme IX).

Compounds of the invention having an amine linker (Compound pp) can beprepared by the method disclosed in Scheme X.

Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions and dosage forms of the invention compriseone or more active ingredients in relative amounts and formulated insuch a way that a given pharmaceutical composition or dosage form can beused for immunosuppression or to treat or prevent inflammatoryconditions, immune disorders, and allergic disorders. Preferredpharmaceutical compositions and dosage forms comprise a compound of anyone of formulas (I) through (VI), or Table 1, or a pharmaceuticallyacceptable prodrug, salt, solvate, or clathrate thereof, optionally incombination with one or more additional active agents.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage formsuitable for mucosal administration may contain a smaller amount ofactive ingredient(s) than an oral dosage form used to treat the sameindication. This aspect of the invention will be readily apparent tothose skilled in the art. See, e.g., Remington's Pharmaceutical Sciences(1990) 18th ed., Mack Publishing, Easton Pa.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms.

The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients can be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines (e.g., N-desmethylvenlafaxineand N,N-didesmethylvenlafaxine) are particularly susceptible to suchaccelerated decomposition. Consequently, this invention encompassespharmaceutical compositions and dosage forms that contain little, ifany, lactose. As used herein, the term “lactose-free” means that theamount of lactose present, if any, is insufficient to substantiallyincrease the degradation rate of an active ingredient. Lactose-freecompositions of the invention can comprise excipients that are wellknown in the art and are listed, for example, in the U.S. Pharmocopia(USP) SP (XXI)/NF (XVI). In general, lactose-free compositions compriseactive ingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. Preferredlactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 379-80. In effect, water andheat accelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizer” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms of the invention comprise acompound of any one of formulas (I) through (VI), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereofin an amount of from about 1 mg to about 1000 mg, preferably in anamount of from about 50 mg to about 500 mg, and most preferably in anamount of from about 75 mg to about 350 mg. The typical total dailydosage of a compound of any one of formulas (I) through (VI), or Table1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof can range from about 1 mg to about 5000 mg per day, preferablyin an amount from about 50 mg to about 1500 mg per day, more preferablyfrom about 75 mg to about 1000 mg per day. It is within the skill of theart to determine the appropriate dose and dosage form for a givenpatient.

Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences (1990) 18th ed., MackPublishing, Easton Pa.

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Onespecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103J and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

Controlled Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

A particular extended release formulation of this invention comprises atherapeutically or prophylactically effective amount of a compound offormula (I) through (VI), or Table 1, or a pharmaceutically acceptablesalt, solvate, hydrate, clathrate, or prodrug thereof, in spheroidswhich further comprise microcrystalline cellulose and, optionally,hydroxypropylmethyl-cellulose coated with a mixture of ethyl celluloseand hydroxypropylmethylcellulose. Such extended release formulations canbe prepared according to U.S. Pat. No. 6,274,171, the entire teachingsof which are incorporated herein by reference.

A specific controlled-release formulation of this invention comprisesfrom about 6% to about 40% a compound of any one of formulas (I) through(VI), or Table 1 by weight, about 50% to about 94% microcrystallinecellulose, NF, by weight, and optionally from about 0.25% to about 1% byweight of hydroxypropyl-methylcellulose, USP, wherein the spheroids arecoated with a film coating composition comprised of ethyl cellulose andhydroxypropylmethylcellulose.

Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

Transdermal, Topical, and Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa. and Introduction to Pharmaceutical Dosage Forms(1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels. Further, transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Combination Therapy

The methods for immunosuppression or for treating or preventinginflammatory conditions, allergic disorders, and immune disorders in apatient in need thereof can further comprise administering to thepatient being administered a compound of this invention, an effectiveamount of one or more other active agents. Such active agents mayinclude those used conventionally for immunosuppression or forinflammatory conditions, allergic disorders, or immune disorders. Theseother active agents may also be those that provide other benefits whenadministered in combination with the compounds of this invention. Forexample, other therapeutic agents may include, without limitation,steroids, non-steroidal anti-inflammatory agents, antihistamines,analgesics, immunosuppressive agents and suitable mixtures thereof. Insuch combination therapy treatment, both the compounds of this inventionand the other drug agent(s) are administered to a subject (e.g., humans,male or female) by conventional methods. The agents may be administeredin a single dosage form or in separate dosage forms. Effective amountsof the other therapeutic agents and dosage forms are well known to thoseskilled in the art. It is well within the skilled artisan's purview todetermine the other therapeutic agent's optimal effective-amount range.

In one embodiment of the invention where another therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount when the other therapeuticagent is not administered. In another embodiment, the effective amountof the conventional agent is less than its effective amount when thecompound of this invention is not administered. In this way, undesiredside effects associated with high doses of either agent may beminimized. Other potential advantages (including without limitationimproved dosing regimens and/or reduced drug cost) will be apparent tothose of skill in the art.

In one embodiment relating to autoimmune, allergic and inflammatoryconditions, the other therapeutic agent may be a steroid or anon-steroidal anti-inflammatory agent. Particularly useful non-steroidalanti-inflammatory agents, include, but are not limited to, aspirin,ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen,flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam, isoxicam; salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophennol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone and pharmaceutically acceptablesalts thereof and mixtures thereof. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAntiinflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9^(th) ed 1996) and GlenR. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19th ed. 1995) which are hereby incorporated by reference intheir entireties.

Of particular relevance to allergic disorders, the other therapeuticagent may be an anthihistamine. Useful antihistamines include, but arenot limited to, loratadine, cetirizine, fexofenadine, desloratadine,diphenhydramine, chlorpheniramine, chlorcyclizine, pyrilamine,promethazine, terfenadine, doxepin, carbinoxamine, clemastine,tripelennamine, brompheniramine, hydroxyzine, cyclizine, meclizine,cyproheptadine, phenindamine, acrivastine, azelastine, levocabastine,and mixtures thereof. For a more detailed description ofanthihistamines, see Goodman & Gilman's The Pharmacological Basis ofTherapeutics (2001) 651-57, 10^(th) ed).

Immunosuppressive agents include glucocorticoids, corticosteroids (suchas Prednisone or Solumedrol), T cell blockers (such as cyclosporin A andFK506), purine analogs (such as azathioprine (Imuran)), pyrimidineanalogs (such as cytosine arabinoside), alkylating agents (such asnitrogen mustard, phenylalanine mustard, buslfan, and cyclophosphamide),folic acid antagonsists (such as aminopterin and methotrexate),antibiotics (such as rapamycin, actinomycin D, mitomycin C, puramycin,and chloramphenicol), human IgG, antilymphocyte globulin (ALG), andantibodies (such as anti-CD3 (OKT3), anti-CD4 (OKT4), anti-CD5,anti-CD7, anti-IL-2 receptor, anti-alpha/beta TCR, anti-ICAM-1,anti-CD20 (Rituxan), anti-IL-12 and antibodies to immunotoxins).

The foregoing and other useful combination therapies will be understoodand appreciated by those of skill in the art. Potential advantages ofsuch combination therapies include a different efficacy profile, theability to use less of each of the individual active ingredients tominimize toxic side effects, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Other Embodiments

The compounds of this invention may be used as research tools (forexample, as a positive control for evaluating other potential CRACinhibitors, or IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, and/or INF-γinhibitors). These and other uses and embodiments of the compounds andcompositions of this invention will be apparent to those of ordinaryskill in the art.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of compounds of the invention. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe purpose and interest of this invention. The following examples areset forth to assist in understanding the invention and should not beconstrued as specifically limiting the invention described and claimedherein. Such variations of the invention, including the substitution ofall equivalents now known or later developed, which would be within thepurview of those skilled in the art, and changes in formulation or minorchanges in experimental design, are to be considered to fall within thescope of the invention incorporated herein.

EXAMPLES

Experimental Rationale

Without wishing to be bound by theory, it is believed that the compoundsof this invention inhibit CRAC ion channels, either directly orindirectly, thereby inhibiting production of IL-2 and other keycytokines involved with inflammatory, allergic and immune responses. Theexamples that follow can be used to demonstrate these properties.

Materials and General Methods

Reagents and solvents for preparing compounds of the invention wereobtained from commercial sources such as Aldrich Chemical Co.(Milwaukee, Wis., USA). ¹H-NMR and ¹³C-NMR spectra typically wererecorded on a Varian 300 MHz NMR spectrometer. Significant peaks weretabulated in the order: δ (ppm): chemical shift, multiplicity (s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broadsinglet), coupling constant(s) in Hertz (Hz) and number of protons.

Patch clamp experiments were performed in the tight-seal whole-cellconfiguration at 21-25° C. High resolution current recordings wereacquired by a computer-based patch clamp amplifier system (EPC-9, HEKA,Lambrecht, Germany). Patch pipettes have resistances between 2-4 MΩafter filling with the standard intracellular solution. Immediatelyfollowing establishment of the whole-cell configuration, voltage rampsof 50-200 ms duration spanning the voltage range of −100 to +100 mV weredelivered at a rate of 0.5 Hz over a period of 300-400 seconds. Allvoltages were corrected for a liquid junction potential of 10 mV betweenexternal and internal solutions when using glutamate as theintracellular anion. Currents were filtered at 2.9 kHz and digitized at10 μs intervals. Capacitive currents and series resistance weredetermined and corrected before each voltage ramp using the automaticcapacitance compensation of the EPC-9. The low resolution temporaldevelopment of membrane currents were assessed by extracting the currentamplitude at −80 mV or +80 mV from individual ramp current records.

Example 1 Synthesis of Representative Exemplary Compounds of thisInvention

In general, the compounds of the invention can be synthesized usingmethods analogous to those described in U.S. patent application Ser. No.10/897,681, filed on Jul. 22, 2004 and U.S. patent application Ser. No.11/233,224, filed on Sep. 21, 2005, the entire teachings of these patentapplications are incorporated herein by reference.

Compound 12,6-Difluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

Into a 50 mL roundbottom flask, was placed 4-methoxyphenylboronic acid(5.4 g, 35.54 mmol). To this was added 5-bromo-pyrazin-2-ylamine (3 g,17.24 mmol). Cu(OAc)₂ (3.45 g, 19.06 mmol) was added, followed byaddition of a solution of DMAP (4.2 g, 34.43 mmol) in CH₂Cl₂ (20 mL).The resulting solution was stirred at room temperature for 12 hours. Thereaction progress was monitored by thin layer chromatography (TLC)(ethyl acetate/petroleum ether=1:2). When the reaction was complete, themixture was filtered, then concentrated under vacuum. The residue wasdissolved in ethyl acetate (EtOAc), then washed with water. The organiclayer was dried over Na₂SO₄, then filtered and concentrated. The crudeproduct was purified by silica gel chromatography (SGC) eluting withethyl acetate/petroleum ether (1:5, v/v) to provide(5-bromo-pyrazin-2-yl)-(4-methoxy-phenyl)-amine (i) (500 mg, yield 10%)as a yellow solid.

Into a 50 mL round bottom flask was placed a solution of(5-bromo-pyrazin-2-yl)-(4-methoxy-phenyl)-amine (i) (180 mg, 0.64 mmol)in acetic acid (AcOH) (2 mL). To this stirred solution was added HNO₃(90 mg) in AcOH (1 mL) at 10° C. dropwise. The temperature was slowlyraised to 35-40° C. in an oil bath until the mixture became brick-redcolor. Cold water was then added and the red crystals were collected andwashed three times with 10 mL of H₂O. The solid was dried in an ovenresulting in 130 mg (62%) of(5-bromo-pyrazin-2-yl)-(4-methoxy-2-nitro-phenyl)-amine (ii) as a redsolid.

Into a 250 mL roundbottom flask, was placed a solution of(5-bromo-pyrazin-2-yl)-(4-methoxy-2-nitro-phenyl)-amine (ii) (3.3 g,9.64 mmol) in dichloromethane (DCM) (50 mL). To the mixture was added Zn(6.5 g, 99.40 mmol). To this stirred mixture was added a solution ofAcOH (6 g, 99.92 mmol) in ethanol (EtOH) (50 mL) dropwise at 0-5° C. Theresulting solution was then stirred at room temperature for 30 minutes.The reaction progress was monitored by TLC (ethyl acetate/petroleumether=1:2). Undissolved material was then filtered off and the filtratewas concentrated under reduced pressure. The resulting solution wasdiluted with 100 mL of H₂O. Adjustment of the pH to 8 was accomplishedby the addition of NaHCO₃. The resulting solution was extracted threetimes with 50 mL each of ethyl acetate (EtOAc) and the combined organiclayers were dried over MgSO₄ and concentrated by evaporation undervacuum using a rotary evaporator. The residue was purified by elutingthrough a silica gel column with a 1:1 EtOAc/petroleum ether (PE)solvent system. This resulted in 1.7 g (60%) ofN1-(5-bromo-pyrazin-2-yl)-4-methoxy-benzene-1,2-diamine (iii) as ayellow solid.

Into a 100 mL roundbottom flask was placedN1-(5-bromo-pyrazin-2-yl)-4-methoxy-benzene-1,2-diamine (iii) (1.3 g,4.40 mmol). To this was added trifluoroacetic acid (TFA) (5 mL) andtrifluoroacetic anhydride (TFAA) (5 mL). The resulting solution wasstirred at 80° C. for 1 hour. The mixture was concentrated. Adjustmentof the pH to 9-10 was accomplished by the addition of K₂CO₃ (10%). Theresulting solution was extracted three times with 50 mL of EtOAc and theorganic layers were combined and dried over Na₂SO₄. After removal of thevolatile components, the residue was taken up by toluene (20 mL)followed by the addition of toluene-4-sulfonic acid (TsOH) (200 mg, 1.16mmol). The resulting solution was stirred at 100° C. for an additional 3hours. The reaction mixture was diluted with EtOAc, then washed withwater. The organic layer was separated and dried over Na₂SO₄, thenconcentrated. The crude product was purified by eluting through a silicagel column with a 1:20 EtOAc/PE solvent system. This resulted in 550 mg(33%) of1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole(iv) as a white solid.

Into a 10 mL sealed tube, was placed1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole(iv) (150 mg, 0.40 mmol). To this was added Cu₂O (30 mg, 0.21 mmol),followed by a saturated solution of NH₃ in ethylene glycol (4 ml). Theresulting solution was stirred at 70° C. for 3 hours, then diluted with30 mL of H₂O and extracted three times with 20 mL of EtOAc. The organiclayers were combined and dried over Na₂SO₄. Removal of the volatilecomponents under reduced pressure afforded the product5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-ylamine (v)(50 mg, yield 40%) as a white solid.

¹H NMR (400 Hz,CDCl3) δ:3.91 (3H, s), 7.13 (1H, d), 7.28 (1H, d), 7.39(1H, s), 8.65 (1H, s), 8.80 (1H, s); ESMS calcd for C₁₃H₁₀F₃N₅O: 309;found: 310 (M+H).

Into a 50 mL round bottom flask, was placed5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-ylamine (v)(30 mg, 0.10 mmol). To this was added 2,6-difluorobenzoic acid (30 mg,0.19 mmol), 1-ethyl-3-[3-dimethylaminopropyl]-carbodiimide (EDC) (100mg, 0.52 mmol) and N,N-dimethylamino-pyridine (DMAP) (70 mg, 0.57 mmol)followed by CHCl₃ (10 mL). The resulting solution was stirred at 55° C.overnight. The reaction progress was monitored by TLC (EtOAc/PE=1:2).After completion, the resultant solution was diluted with 20 mL ofCHCl₃, washed with 20 mL of H₂O and dried over Na₂SO₄. After removal ofthe solvent and volatile components under reduced pressure, the residuewas purified by eluting through a silica gel column with a 1:5 EtOAc/PEsolvent system. This resulted in 20 mg (46%) of2,6-difluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide(Compound 1) as a white solid.

¹H NMR (300 Hz,CDCl3) δ: 3.90 (3H, s),6.96(1H, d),7.09 (2H, d),7.41 (1H,s), 7.54 (1H, t), 7.56 (1H, d), 8.53 (1H, s), 8.63 (1H, s), 9.79 (1H,s), 12.43 (1H, s) ppm; ESMS calcd for C₂₀H₁₂F₅N₅O₂: 449; found: 450(M+H).

Compound 46[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-benzyl)-amine

Into a 50 mL roundbottom flask, was placed a solution of1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole(iv) (50 mg, 0.13 mmol) in DMSO (5 mL)(1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole(iv) was prepared as described for Compound 1 above). To this was added2-methyl-benzylamine (40 mg, 0.33 mmol) followed by CuI (10 mg, 0.05mmol). To the mixture was added L-proline (20 mg, 0.17 mmol). Theresulting solution was held at 50° C. for 1 hr while the reactionprogress was monitored by TLC (EtOAc/PE=1:2). After completion, thereaction mixture was allowed to cool to room temperature, then washedtwice with H₂O (30 mL each). After removal of the volatile componentsunder vacuum, the residue was purified by eluting through a silica gelcolumn with a 1:10 EtOAc/PE solvent system. This resulted in 25 mg (44%)of the product[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-benzyl)-amine(Compound 46) as a white solid.

¹H NMR (400 MHz, DMSO): δ 2.34 (3H, s), 3.82 (3H, s), 4.53 (2H,d, J=6),7.06 (1H,d, J=9),7.17(2H,d, J=9), 7.19 (1H, s), 7.28 (1H,d, J=9), 7.32(1H, d, J=9), 7.33 (1H, d, J=9), 8.03(1H,s), 8.06 (1H, s), 8.30 (1H,s)ppm; ESMS calcd for C₂₁H₁₈F₃N₅O: 413; found: 414 (M+H).

Compound 852-Bromo-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

Into a 50 mL round bottom flask, was placed a solution of 2-bromobenzoylchloride (500 mg, 2.28 mmol) in CH₂Cl₂ (5 mL). To the mixture was added5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-ylamine (v)(100 mg, 0.32 mmol) (Preparation of5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-ylamine (v)is described for Compound 1 above). The resulting solution was allowedto react, with stirring, for 8 hours while the temperature wasmaintained at room temperature. The reaction progress was monitored byTLC (EtOAc/PE=1:2). After standard workup, the crude product waspurified by eluting through a silica gel column with a 1:5 EtOAc/PEsolvent system. This resulted in 50 mg (21%) of(E)-2-bromo-N-[1-(2-bromo-benzoyl)-5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-1H-pyrazin-2-ylidene]-benzamide(vi) as a white solid.

Into a 50 mL round bottom flask was placed(E)-2-bromo-N-[1-(2-bromo-benzoyl)-5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-1H-pyrazin-2-ylidene]-benzamide(vi) (50 mg, 0.07 mmol). To this was added LiOH (100 mg), followed byEtOH (25 mL). The resulting solution was allowed to react, withstirring, for 30 minutes while the temperature was maintained at roomtemperature. The reaction progress was monitored by TLC (EtOAc/PE=1:2).After completion, the resulting solution was diluted with 15 mL of H₂Oand extracted two times with 10 mL of EtOAc. The organic layers werecombined and dried over Na₂SO₄. After removal of the solvent andvolatile components under vacuum, the residue was purified by elutingthrough a silica gel column with a 1:6 EtOAc/PE solvent system. Thisresulted in 10 mg (27%) of the final product2-bromo-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide(Compound 85) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ 3.87 (3H, s), 7.12 (1H, d, J=9), 7.44 (1H,s), 7.55 (1H, d, J=9), 8.91 (1H, s), 9.50 (1H, s), 11.83 (1H, s), 7.75(1H, d, J=9), 7.49 (1H, d, J=9), 7.53 (1H, t), 7.65 (1H, d, J=9); ESMScalcd for C₂₀H₁₃BrF₃N₅O₂: 491; found: 492 (M+H).

Compound 864-Fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

Into a 50 mL 3-necked round bottom flask, purged and maintained with aninert atmosphere of nitrogen, was placed a solution of1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole(iv) (100 mg, 0.27 mmol) in 1,4-dioxane (30 mL). To this was added4-fluorobenzamide (80 mg, 0.58 mmol), K₃PO₄ (250 mg, 1.18 mmol), CuI (10mg, 0.05 mmol) and ethane-1,2-diamine (EDA) (5 mg, 0.08 mmol). Theresulting solution was stirred at reflux overnight. The reactionprogress was monitored by TLC (EtOAc/PE=1:2). When the reaction had goneto completion, the mixture was filtered to remove the solid components,then concentrated under vacuum. The residue was dissolved in EtOAc, thenwashed with water. The organic layer was dried over Na2SO4, thenconcentrated to yield a crude product. The crude product was purified byeluting through a column with a 1:6 EtOAc/PE solvent system. Thisresulted in 60 mg (52%) of4-fluoro-N-(5-(5-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)pyrazin-2-yl)benzamide(Compound 86) as a white solid.

¹HNMR (300 Hz, DMSO-d₆) δ: 3.80 (s, 3H), 7.09 (d, 1H, J=9), 7.33-7.41(m, 4H), 8.11 (t, 2H, J=7), 8.88(s, 1H), 9.45 (s, 1H), 11.58 (s, 1H)ppm; ESMS calcd for C₂₀H₁₃F₄N₅O₂: 431; found: 432 (M+H).

The following examples were synthesized in a similar manner as describedabove:

Compound 33-Fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-isonicotinamide

¹H NMR (DMSO): δ 3.86 (3H,s), 7.12 (1H,d), 7.47 (2H,d), 7.77 (1H,d),8.62 (1H,d), 8.80 (1H,s), 8.94 (1H,s), 9.50 (1H,s), 12.00 (1H,s) ppm;ESMS calcd for C₁₉H₁₂F₄N₆O₂: 432; found: 433 (M+H).

Compound 52-Fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR(DMSO): δ 3.84(3H, s), 7.11(1H, d, J=9), 7.35(2H, m), 7.44(2H, d,J=9), 7.62(1H, m), 7.75(1H, d, J=9), 8.89(1H, s), 9.49 (1H, s),11.65(1H, s) ppm; ESMS calcd for C₂₀H₁₃F₄N₅O₂: 431; found: 432 (M+H).

Compound 72,4-Difluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz,CDCl₃) δ: 3.91(3H,s), 7.00 (1H,d, J=9), 7.10 (2H,m),7.39(1H,s), 8.28 (1H, dd), 8.55 (1H,s), 9.24(1H,d),9.79(1H,s) ppm; ESMScalcd for C₂₀H₁₂F₅N₅O₂: 449; found: 450 (M+H).

Compound 94-Chloro-2-fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (400 MHz, DMSO-d6): δ 3.86 (3H, s), 7.13 (1H, d, J=9), 7.45 (1H,d, J=9), 7.46 (1H, d, J=9), 7.48 (1H, d, J=9), 7.68 (1H, d, J=9), 7.83(1H, d, J=9), 9.49 (1H, s), 8.92 (1H, s), 11.75 (1H, s) ppm; ESMS calcdfor C₂₀H₁₂ClF₄N₅O₂: 465; found: 466 (M+H).

Compound 10N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-benzamide

¹H NMR (300 Hz, DMSO): δ 2.45 (3H,s), 3.86 (3H,s), 7.14 (1H,d), 7.32(1H,d), 7.35 1H, t), 7.43 (1H,s), 7.45 (1H,t,), 7.48 (1H,d), 7.58(1H,d), 8.89 (1H,s), 9.53 (1H,s), 11.58 (1H,s) ppm; ESMS calcd forC₂₁H₁₆F₃N₅O₂: 427; found: 428 (M+H).

Compound 37(2,6-Difluoro-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine

¹H NMR (400 MHz, DMSO): δ 3.73 (3H,S), 4.00 (2H,d), 6.62 (1H,dd), 6.77(1H,dd), 7.03 (1H,dd), 7.21 (2H, dd), 7.59 (1H, dd), 7.90 (1H, s), 7.9(1H, s) ppm; ESMS calcd for C₂₀H₁₄F₅N₅O: 435; found: 436 (M+H).

Compound 41(2-Fluoro-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine

¹H NMR (300 MHz, DMSO-d6): δ 3.73 (3H, s), 4.0 (2H, d, J=6), 7.9 (1H,s), 7.9 (1H, s), 7.21 (2H, s), 7.59 (1H, dd), 6.77 (1H, dd), 6.91(1H,dd), 7.04 (1H, dd), 7.05 (1H, dd) ppm; ESMS calcd for C₂₀H₁₅F₄N₅O: 417;found: 418 (M+H).

Compound 73Cyclohexylmethyl-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine

¹H NMR (400 MHz, DMSO) δ: 0.98-1.79(11H, m), 3.18 (2H, t, J=8), 3.83(3H, s), 7.08 (1H, d, J=8), 7.28 (1H, s), 7.39 (1H, d, J=8), 7.72(1H,t,J=8) 7.94 (1H, s), 8.25 (1H, s) ppm; ESMS calcd for C₂₀H₂₂F₃N₅O: 406;found: 407 (M+H).

Compound 87(2-Chloro-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine

¹H NMR(400 Hz, DMSO): δ 3.82 (3H,s), 4.64 (2H,d, J=5), 7.1(1H,d, J=9),7.27 (1H, d, J=9), 7.31(1H,d, J=9), 7.32 (1H, t, J=9), 7.33 (1H, t,J=9), 7.39 (1H, s), 7.47 (1H, d, J=9), 8.08 (1H, s), 8.2 (1H, t, J=9),8.31(1H,s) ppm; ESMS calcd for C₂₀H₁₅ClF₃N₅O: 433; found: 434 (M+H).

Compound 883-Fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR(400 Hz, DMSO): δ 3.85 (3H,s), 7.15 (1H,d, J=9), 7.42(1H,d, J=9),7.45(1H,s), 7.5(1H,t), 7.6(1H,d, J=9), 7.9(1H,d, J=9), 7.95(1H,d, J=9),8.95(1H,s), 9.52(1H,s), 11.68(1H,s) ppm; ESMS calcd for C₂₀H₁₃F₄N₅O₂:431; found 432 (M+H).

Compound 89(4-Fluoro-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine

¹H NMR(400 MHz,DMSO) δ 3.73 (3H,s), 4.32 (2H,s), 6.77(1H,d, J=9),6.85(2H,d, J=9), 7.04(2H,d, J=9), 7.21(1H,s), 7.59(1H,d, J=9),7.9(2H,s), 11.0(1H,s) ppm; ESMS calcd for C₂₀H₁₅F₄N₅O: 417; found: 418(M+H).

Compound 90(4-Methoxy-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine

¹NMR(400 MHz, DMSO) δ:3.73 (6H,s), 4.32 (2H,s), 6.65 (2H,d, J=9),6.77(1H,s), 6.95(2H,d, J=9), 7.21(1H,s), 7.59(1H,d, J=9), 7.9 (2H,s),11.0(1H,s) ppm; ESMS calcd for C₂₁H₁₈F₃N₅O₂: 429; found: 430 (M+H).

Compound 914-Chloro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz,DMSO-D6) δ 3.86 (3H, s), 7.16 (1H, d, J=9), 7.47 (2H, d,J=9), 7.66 (2H, d, J=9), 8.11 (2H, d, J=9), 8.94 (1H, s), 9.51 (1H, s),11.69 (1H, s) ppm; ESMS calcd for C₂₀H₁₃ClF₃N₅O₂: 447; found: 448 (M+H).

Compound 92N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2,3-dimethyl-benzamide

¹H NMR (DMSO): δ 2.31 (6H,s),3.86 (3H,s), 7.12(1H,d, J=9), 7.24(1H,m),7.34(2H,m), 7.47(2H,d, J=9), 8.88(1H,s), 9.53 (1H,s), 11.58(1H,s) ppm;ESMS calcd for C₂₂H₁₈F₃N₅O₂: 441; found: 442 (M+H).

Compound 934-Cyano-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR(DMSO): δ 3.86(3H, s), 7.16(1H, d), 7.47(2H, m), 8.04(2H, d, J=9),8.19(2H, d, J=9), 8.95 (1H, s), 9.52(1H, s), 11.86(1H, s) ppm; ESMScalcd for C₂₁H₁₃F₃N₆O₂: 438; found: 439 (M+H).

Compound 94N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2,4-dimethyl-benzamide

¹H NMR (DMSO): δ 2.34 (3H,s), 2.42(3H,s), 3.86(3H,s), 7.15 (3H,m),7.49(3H,m), 8.88(1H,s), 9.51(1H,s), 11.48(1H,s) ppm; ESMS calcd forC₂₂H₁₈F₃N₅O₂: 441; found: 442 (M+H).

Compound 95N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-methylsulfanyl-benzamide

¹H NMR(DMSO-d6): δ 2.58 (3H, s), 3.86 (3H, s), 7.13 (1H, d, J=9), 7.49(4H, m), 7.81 (1H, d, J=9), 7.93 (1H, s), 8.93 (1H, s), 9.51 (1H, s),11.66 (1H, s) ppm; ESMS calcd for C₂₁H₁₆F₃N₅O₂S: 459; found: 460 (M+H).

Compound 963-Chloro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (400 MHz, CDCl₃): δ 3.89 (3H, s), 7.08 (1H, d, J=8), 7.24 (1H,s), 7.37 (1H, d, J=8), 7.52 (1H, d, J=8), 7.63 (1H, d, J=8), 7.83 (1H,s), 7.97 (1H, s), 8.52 (1H, s), 8.64 (1H, s), 9.77 (1H, s) ppm; ESMScalcd for C₂₀H₁₃ClF₃N₅O₂: 447; found: 448 (M+H).

Compound 97N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-4-nitro-benzamide

¹H NMR (300 MHz, DMSO-d6): δ 3.86 (s, 3H), 7.15 (d, 1H), 7.45 (s, 1H),7.48 (d, 1H), 8.29 (d, 2H), 8.40 (d, 2H), 8.97(s, 1H), 9.53(s, 1H),11.96(s, 1H) ppm; ESMS calcd for C₂₀H₁₃F₃N₆O₄: 458; found: 459 (M+H).

Compound 98N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-nitro-benzamide

¹H NMR (300 MHz, DMSO-d6): δ 3.87 (s, 3H), 7.15 (d, 1H, J=9), 7.46 (s,1H), 7.48 (d, 1H, J=9), 7.88 (m, 2H), 8.50 (d, 2H, J=9), 8.91 (s, 1H),8.97 (s, 1H), 9.53 (s, 1H), 12.01 (s, 1H) ppm; ESMS calcd forC₂₀H₁₃F₃N₆O₄: 458; found: 459 (M+H).

Compound 992-Chloro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, CDCl₃); δ 3.92 (3H, s), 7.10 (1H, d, J=8), 7.26 (1H, d,J=8), 7.40 (1H, s), 7.56-7.53 (3H, m), 7.92 (1H, d, J=8), 8.53 (1H, s),8.94 (1H, s), 9.81 (1H, s) ppm; ESMS calcd for C₂₀H₁₃ClF₃N₅O₂: 447;FOUND: 448 (m+H).

Compound 100(2-Chloro-6-fluoro-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine

¹H NMR (300 MHz, DMSO-d6): δ 3.73 (3H, s), 4.0 (1H, s), 4.32 (1H, dd),6.73 (1H, dd), 6.77 (1H, dd), 6.92 (1H, dd), 6.99 (1H, m), 7.21 (2H, s),7.59 (1H, dd), 7.9 (1H, s), 7.9 (1H, s) ppm; ESMS calcd forC₂₀H₁₄ClF₄N₅O: 451; found: 452 (M+H).

Compound 1013-Cyano-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (400 MHz, DMSO): δ 3.73 (3H, s), 7.21 (1H, s), 6.77 (1H,dd), 7.59(1H,dd), 7.90 (1H,s), 7.90 (1H,s), 8.0 (1H,s), 8.20 1H,dd), 8.23 (1H,s),7.76 (1H,dd), 7.62 (1H,dd) ppm; ESMS calcd for C₂₁H₁₃F₃N₆O₂: 438; found:439 (M+H).

Compound 102(2-Methoxy-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine

¹H NMR (400 Hz, DMSO): δ 3.82 (6H,s), 4.52 (2H,d, J=6),6.91 (1H,d, J=9),7.02 (1H,t), 7.07 (1H, d, J=9), 7.26 (1H, d, J=9), 7.28 (1H, t, J=9),7.29 (1H, d, J=9), 7.39 (1H, s), 8.0 (1H,t), 8.02 (1H,s), 8.28 (1H, s)ppm; ESMS calcd for C₂₁H₁₈F₃N₅O₂: 429; found: 430 (M+H).

Compound 103(3-Methoxy-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine

¹H NMR (400 Hz, DMSO): δ 3.73 (3H,s), 3.82 (3H,s), 4.53 (2H,d), 6.83(1H,d), 6.94 (1H,s), 6.95 (1H,d), 7.04 (1H,d), 7.24 (1H,t), 7.27 (1H,d),7.39 (1H,s), 8.01 (1H,s), 8.18 (1H,t), 8.30 (1H,s) ppm; ESMS calcd forC₂₁H₁₈F₃N₅O2: 429; found: 430 (M+H).

Compound 1043-Methoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (DMSO): δ 3.87 (6H, s), 7.15 (1H,d, J=8), 7.25 (1H,d, J=8), 7.47(3H,m), 7.70 (2H,m), 8.85 (1H,s), 9.50 (1H,s), 11.60 (1H,s) ppm; ESMScalcd for C₂₁H₁₆F₃N₅O₃: 443; found: 444 (M+H).

Compound 105[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-pyridin-4-ylmethyl-amine

¹H NMR (400 Hz, DMSO): δ 3.81 (3H,s), 4.62 (2H,d), 7.07 (1H,d), 7.27(1H,d), 7.37 (2H,d), 7.38 (1H,d), 8.06 (1H,s), 8.29 (1H,s), 8.33 (1H,t),8.50 (2H,d) ppm; ESMS calcd for C₁₉H₁₅F₃N₆O: 400; found: 401 (M+H).

Compound 1064-Ethyl-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (DMSO): δ 1.23 (3H, m), 2.70 (2H, m), 3.86 (3H, s), 7.12 (1H, d,J=8), 7.39 (4H, m), 8.01 (2H, d, J=8), 8.92 (1H, s), 9.52 (1H, s), 11.49(1H, s) ppm; ESMS calcd for C₂₂H₁₈F₃N₅O₂: 441; found: 442 (M+H).

Compound 1074-Bromo-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, CDCl₃): δ 3.92 (3H,s), 7.10 (1H, d), 7.25 (1H, d), 7.39(1H,s), 7.75 (2H,d), 7.90 (2H,d), 8.54 (1H,s), 8.71 (1H,s), 9.79(1H,s)ppm; ESMS calcd for C₂₀H₁₃BrF₃N₅O₂: 491; found: 492 (M+H).

Compound 1083-Bromo-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, CDCl₃): δ 3.92 (3H,s), 7.16 (1H,d), 7.26 (1H,d), 7.40(1H,s), 7.47 (1H,t), 7.80 (1H,d), 7.90 (1H,d), 8.15 (1H,s), 8.54 (1H,s),8.72 (1H,s), 9.79 (1H,s) ppm; ESMS calcd for C₂₀H₁₃BrF₃N₅O₂: 491; found:492 (M+H).

Compound 109N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-4-propyl-benzamide

¹H NMR (DMSO): δ 0.90 (3H, m), 1.65 (2H, m), 2.64 (2H, m), 3.84 (3H, s),7.11 (1H, d), 7.35 (2H, d), 7.42 (1H, d), 7.45 (1H, s), 8.00 (2H, d),8.90 (1H, s), 9.50 (1H, s), 11.48 (1H, s) ppm; ESMS calcd forC₂₃H₂₀F₃N₅O₂: 455; found: 456 (M+H).

Compound 1102,4-Dichloro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, CDCl₃): δ3.92 (3H,s), 7.10 (1H,d, J=8), 7.25 (1H,d,J=8), 7.39 (1H, s), 7.48 (1H, d, J=8), 7.58 (1H, s), 7.89 (1H, d, J=8),8.54 (1H, s), 8.94 (1H, s), 9.78 (1H,s) ppm; ESMS calcd forC₂₀H₁₂Cl₂F₃N₅O₂: 481; found: 482 (M+H).

Compound 1112-Methoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 Hz, DMSO): δ 3.86 (3H,s), 3.99 (3H,s), 7.12 (1H,d), 7.16(1H,d), 7.28 (1H,d), 7.45 (1H,s), 7.46 (1H,t,), 7.60 (1H,t), 7.85(1H,d), 8.90 (1H,s), 9.57 (1H,s), 11.11 (1H,s) ppm; ESMS calcd forC₂₁H₁₆F₃N₅O₃: 443; found: 444 (M+H).

Compound 1123-Iodo-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (400 MHz, DMSO-D6): δ 3.86 (3H, s), 7.13 (1H, d, J=8), 7.37 (1H,d, J=8),7.44 (1H, d, J=8), 7.48 (1H, d, J=8), 8.01 (1H, d, J=8), 8.03(1H, d, J=8), 8.43 (1H, s), 8.94 (1H, s), 9.50 (1H, s), 11.70 (1H, s)ppm; ESMS calcd for C₂₀H₁₃F₃IN₅O₂: 539; found: 540 (M+H).

Compound 1132,3-Dichloro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (400 MHz, CDCl₃): δ 3.86 (3H,s), 7.14 (1H,d), 7.47 (1H,s), 7.52(1H,t), 7.55 (1H,d), 7.82 (1H,d), 8.92 (1H,s), 9.51 (1H,s), 11.93 (1H,s)ppm; ESMS calcd for C₂₀H₁₂Cl₂F₃N₅O₂: 481; found: 482 (M+H).

Compound 114N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-isophthalamicacid ethyl ester

¹H NMR (300 Hz, CDCl₃): δ 1.46 (3H,t, J=7), 3.83 (3H,s), 4.48 (2H,q),7.13 (1H,d, J=8), 7.29 (1H,d, J=8), 7.40 (1H,s), 7.69 1H,t, J=8), 8.24(1H,d, J=8), 8.35 (1H,d, J=8), 8.56 (1H,s), 8.63 (1H,s), 8.82 (1H,s),9.83 (1H,s) ppm; ESMS calcd for C₂₃H₁₈F₃N₅O₄: 485; found: 486 (M+H).

Compound 115Benzyl-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine

¹H NMR (300 Hz, DMSO): δ 3.85 (3H,s), 4.58 (2H,d), 7.07 (1H,d), 7.28(2H,d), 7.30 (1H,t), 7.34 (1H,d), 7.39 (2H,d), 7.41 (1H,s), 8.02 (1H,s),8.22 (1H,t), 8.31 (1H,s) ppm; ESMS calcd for C₂₀H₁₆F₃N₅O: 399; found:400 (M+H).

Compound 116N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl-benzamide

¹H NMR (400 MHz, CDCl₃): δ 2.50 (3H, s), 3.92 (3H, s), 7.15 (1H, d, 7.25(1H, s), 7.40 (1H, d), 7.46 (1H, s), 7.48 (1H, m), 7.81 (1H, s), 7.82(1H, d), 8.53 (1H, s), 8.74 (1H, s), 9.82 (1H, s) ppm; ESMS calcd forC₂₁H₁₆F₃N₅O₂: 427; found: 428 (M+H).

Compound 1174-Butyl-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (400 MHz, CDCl₃): δ 0.98 (3H, m), 1.40 (2H, m), 1.67 (2H, m),2.74 (2H, m), 3.92 (3H, s), 7.12 (1H, d, J=8), 7.26 (1H, s), 7.37 (1H,d, J=8), 7.39 (2H, s), 7.91 (2H, s), 8.52 (1H, s), 8.73 (1H, s), 9.82(1H, s) ppm; ESMS calcd for C₂₄H₂₂F₃N₅O₂: 469; found: 470 (M+H).

Compound 118N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-4-methyl-benzamide

¹H NMR (400 MHz, CDCl₃): δ 2.49 (3H, d), 3.91 (3H, s), 7.09 (1H, d),7.25 (1H, s), 7.37 (2H, d), 7.39 (1H, d), 7.90 (2H, d), 8.51 (1H, s),8.74 (1H, s), 9.82 (1H, s) ppm; ESMS calcd for C₂₁H₁₆F₃N₅O₂: 427; found:428 (M+H).

Compound 119N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-4-methylsulfanyl-benzamide

¹H NMR (400 MHz, CDCl₃): δ 2.58 (3H, s), 3.91 (3H, s), 7.09 (1H, d),7.25 (1H, s), 7.37 (1H, d), 7.39 (2H, d), 7.90 (2H, d), 8.52 (1H, s),8.72 (1H, s), 9.81 (1H, s) ppm; ESMS calcd for C₂₁H₁₆F₃N₅O₂S: 459;found: 460 (M+H).

Compound 1204-Methoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

1HNMR (400 MHz, CDCl3) δ: 3.92 (6H, s), 7.04 (1H, d, J=8), 7.10 (2H, d,J=8), 7.24 (1H, s), 7.39 (1H, d, J=8), 7.98 (2H, d, J=8), 8.51 (1H, s),8.71 (1H, s), 9.81 (1H, s) ppm; ESMS calcd for C₂₁H₁₆F₃N₅O₃: 443; found:444 (M+H).

Compound 121N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3,5-dimethyl-benzamide

¹H NMR (CDCl₃): δ 2.45 (6H, s), 3.91 (3H, s), 7.09 (1H, d), 7.12 (1H,s), 7.29 (1H, d), 7.40 (1H, s), 7.59 (2H, s), 8.52 (1H, s), 8.69 (1H,s), 9.81 (1H, s) ppm; ESMS calcd for C₂₂H₁₈F₃N₅O₂: 441; found: 442(M+H). Compound 122:N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2,5-dimethyl-benzamide

¹H NMR (CDCl₃): δ 2.41 (3H, s), 2.56 (3H, s), 3.91 (3H, s), 7.10 (1H,d), 7.22 (2H, d), 7.39 (1H, s), 7.44 (1H, s), 8.41 (1H, s), 8.49 (1H,s), 9.80 (1H, s) ppm; ESMS calcd for C₂₂H₁₈F₃N₅O₂: 441; found: 442(M+H).

Compound 1232-Ethoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (CDCl₃): δ 1.71 (3H, m), 3.91 (3H, s), 4.38 (2H, m), 7.08 (1H, d,J=8), 7.09 (1H, d), 7.16 (2H, m), 7.22 (1H, s), 7.56 (1H, m), 8.34 (1H,d), 8.51 (1H, s), 9.85 (1H, s), 11.04 (1H, s) ppm; ESMS calcd forC₂₂H₁₈F₃N₅O₃: 457; found: 458 (M+H).

Compound 1242,4-Dimethoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, CDCl₃): δ 3.86 (3H,s), 3.88 (3H,s), 4.05 (3H,s), 6.75(1H,s), 6.77 (1H,d, J=9), 7.14 (1H,d, J=9), 7.43 (1H,s), 7.46 (1H,d,J=8), 7.95 (1H,d, J=8), 8.88 1H,s), 9.57 (1H,s), 10.90 (1H,s) ppm; ESMScalcd for C₂₂H₁₈F₃N₅O₄: 473; found: 474 (M+H).

Compound 125N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-trifluoromethyl-benzamide

¹H NMR (300 MHz, DMSO): δ 3.86 (3H, s), 7.13 (1H, d, J=8), 7.45 1H, s),7.48 (1H, d, J=8), 7.82 (1H, m), 8.02 (1H, d, J=8), 8.37 (1H, d, J=8),8.45 (1H, s), 8.96 (1H, s), 9.53 (1H, s), 11.90 (1H, s) ppm; ESMS calcdfor C₂₁H₁₃F₆N₅O₂: 481; found: 482 (M+H).

Compound 1263,4-Dimethoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, CDCl₃): δ 3.87 (9H,s), 7.35 (2H,m), 7.45 (2H,m), 7.75(2H,m), 8.92 (1H,s), 9.52 (1H,s), 11.47 (1H,s) ppm; ESMS calcd forC₂₂H₁₈F₃N₅O₄: 473; found: 474 (M+H).

Compound 1272-Fluoro-4-methoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, DMSO): δ 3.86 (6H,s), 6.95 (2H,m), 7.03 (1H,d), 7.132H, m), 7.50 (1H,m), 8.90 (1H,s), 9.50 (1H,s), 11.34 (1H,s) ppm; ESMScalcd for C₂₁H₁₅F₄N₅O₃: 461; found: 462 (M+H).

Compound 1282,3-Dimethoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (DMSO): δ 3.86 (3H, s), 3.91 (6H, s), 7.12 (1H, d, J=8), 7.30(3H,m), 7.46 (2H,d, J=8), 8.89 (1H, s), 9.55 (1H, s), 11.33 (1H, s) ppm;ESMS calcd for C₂₂H₁₈F₃N₅O₄: 473; found: 474 (M+H).

Compound 1293,5-Dimethoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, DMSO): δ 3.85 (9H,s), 6.77 (1H,s), 7.15 (1H,d), 7.26(2H,s), 7.45 (2H,m), 8.94 (1H,s), 9.52 (1H,s), 11.58 (1H,s) ppm; ESMScalcd for C₂₂H₁₈F₃N₅O₄: 473; found: 474 (M+H).

Compound 1305-Bromo-2-fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (DMSO): δ 3.85 (3H, s), 7.12 (1H, d, J=8), 7.16 (1H, d, J=8),7.38 (2H, d, J=8), 7.79 (1H, d, J=8), 7.96 (1H, s), 8.89 (1H, s), 9.46(1H, s), 11.82 (1H, s) ppm; ESMS calcd for C₂₀H₁₂BrF₄N₅O₂: 509; found:510 (M+H).

Compound 131N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-4-pentyl-benzamide

¹H NMR (DMSO): δ 0.85 (3H, m), 1.31 (4H, m), 1.62 (2H, m), 2.65 (2H, m),3.86 (3H, s), 7.12 (1H, d), 7.15 (2H, d), 7.43 (2H, d), 8.00 (2H, d),8.91 (1H, s), 9.51 (1H, s), 11.48 (1H, s) ppm; ESMS calcd forC₂₅H₂₄F₃N₅O₂: 483 found: 484 (M+H).

Compound 1324-tert-Butyl-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, DMSO): δ 1.34 (9H,s), 3.86 (3H,s), 7.12 (1H,d, J=8),7.44 (2H, d, J=8), 7.57 (1H,s), 7.60 (1H, d, J=8), 8.03 (2H, d, J=8),8.92 (1H, s), 9.52 (1H, s), 11.52 (1H, s) ppm; ESMS calcd forC₂₄H₂₂F₃N₅O₂: 469; found: 470 (M+H).

Compound 1334-Ethoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, DMSO): δ 1.36 (3H,m), 3.86 (3H,s), 4.14 (2H,m), 7.06(2H,d), 7.09 (1H,d), 7.45 (2H,d), 8.09 (2H,d), 8.91 (1H,), 9.50 (1H,s),11.42 (1H,s) ppm; ESMS calcd for C₂₂H₁₈F₃N₅O₃: 457; found: 458 (M+H).

Compound 1344-Chloro-2-methoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (DMSO): δ 3.85 (3H, s), 3.98 (3H, s), 7.12 (1H, d), 7.18 (1H, d),7.35 (1H, s), 7.43 (1H, s), 7.46 (1H, d), 7.79 (1H, d), 8.89 (1H, s),9.53 (1H, s), 11.11 (1H, s) ppm; ESMS calcd for C₂₁H₁₅ClF₃N₅O₃: 477;found: 478 (M+H).

Compound 135N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-3-nitro-benzamide

¹H NMR (DMSO): δ 2.50 (3H, s), 3.85 (3H, s), 7.12 (1H, s), 7.43 (1H, s),7.46 (1H, d), 7.60 (1H, t), 7.86 (1H, d), 8.03 (1H, d), 8.90 (1H, s),9.53 (1H, s) ppm; ESMS calcd for C₂₁H₁₅F₃N₆O₄: 472; found: 473 (M+H).

Compound 1362,4,5-Trimethoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, DMSO): δ 3.79 (3H,s), 3.85 (3H,s), 3.93 (3H,s), 4.08(3H,s), 6.90 (1H, s), 7.14 (1H,d), 7.44 (2H,d), 7.55 (1H,s), 8.88(1H,s), 9.58 (1H,s) ppm; ESMS calcd for C₂₃H₂₀F₃N₅O₅: 503; found: 504(M+H).

Compound 137N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-4-trifluoromethyl-benzamide

¹H NMR (DMSO): δ 3.85 (3H, s), 7.14 (1H, d), 7.46 (1H, s), 7.47 (1H, d),7.93 (2H, d), 8.24 (2H, d), 8.95 (1H, s), 9.52 (1H, s) ppm; ESMS calcdfor C₂₁H₁₃F₆N₅O₂: 481; found: 482 (M+H).

Compound 1382-Bromo-4-fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (CDCl₃): δ 3.86 (3H, s), 7.12 (1H, d, J=8), 7.42 (1H, d, J=8),7.46 (1H, s), 7.49 (1H, s), 7.75 (2H, d, J=8), 8.90 (1H, s), 9.50 (1H,s), 11.83 (1H, s) ppm; ESMS calcd for C₂₀H₁₂BrF₄N₅O₂: 509; found: 510(M+H).

Compound 1394-Chloro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-nitro-benzamide

¹H NMR (CDCl₃, 300 MHZ): δ 3.90 (3H, s), 7.09 (1H, d), 7.38 (1H, s),7.78 (1H, d), 8.12 (1H, d), 8.50 (1H, s), 8.55 (1H, s), 8.70 (1H, s),9.76 (1H, s) ppm; ESMS calcd for C₂₀H₁₂ClF₃N₆O₄: 492; found: 493 (M+H).

Compound 140N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-4-methyl-3-nitro-benzamide

¹H NMR (300 MHz, CDCl₃): δ 2.73 (3H,s), 3.90 (3H,s), 7.10 (1H,d, J=9),7.38 (1H,s), 7.58 (1H,d), 8.14 (1H,d), 8.55 (2H,d), 8.79 (1H,s), 9.78(1H,s) ppm; ESMS calcd for C₂₁H₁₅F₃N₆O₄: 472; found: 473 (M+H).

Compound 1414-Isopropyl-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, DMSO): δ 1.26 (6H,d), 3.00 (1H,m), 3.86 (3H,s), 7.13(1H,d, J=8), 7.45 (4H,m), 8.03 (2H,d), 8.92 (1H,s), 9.52 (1H,s), 11.50(1H,s) ppm; ESMS calcd for C₂₃H₂₀F₃N₅O₂: 455; found: 456 (M+H).

Compound 142N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl-2-nitro-benzamide

¹H NMR (300 MHz, CDCl₃): δ 2.49 (3H,s), 3.91 (3H,s), 7.12 (1H,d), 7.26(1H,d, J=8), 7.38 (1H,s), 7.61 (3H, m), 8.54 (2H, d, J=8), 9.69 (1H, s)ppm; ESMS calcd for C₂₁H₁₅F₃N₆O₄: 472; found: 473 (M+H).

Compound 1432,4,5-Trifluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (DMSO): δ 3.85 (3H, s), 7.12 (1H, d, J=8), 7.46 (2H, s), 7.77(1H, s), 7.79 (1H, s), 8.93 (1H, s), 9.48 (1H, s), 11.79 (1H, s) ppm;ESMS calcd for C20H11F6N5O2: 467; found: 468 (M+H).

Compound 1442-Methoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-4-trifluoromethyl-benzamide

¹H NMR (300 MHz, CDCl₃): δ 3.91 (3H,s), 4.23 (3H, s), 7.11 (1H,d, J=8),7.26 (1H,d, J=8), 7.35 (1H,s), 7.40 (1H,s), 7.48 (1H,d, J=8), 8.46(1H,d, J=8), 8.55 (1H,s), 9.84 (1H,s), 10.58 (1H,s) ppm; ESMS calcd forC₂₂H₁₅F₆N₅O₃: 511; found: 512 (M+H).

Compound 145N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-trifluoromethyl-benzamide

¹H NMR (CDCl₃): δ 3.90 (3H,s), 7.08 (1H,d, J=8), 7.37 (1H,s), 7.70(3H,m), 7.82 (1H,d, J=8), 8.38 (1H, s), 8.49 (1H, s), 9.75 (1H, s) ppm;ESMS calcd for C₂₁H₁₃F₆N₅O₂: 481; found: 482 (M+H).

Compound 146N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-5-nitro-benzamide

¹H NMR (DMSO): δ 11.85 (1H, s), 9.46 (1H, s), 8.84 (1H, s), 8.46 (1H,s), 8.26 (1H, d, J=8), 7.59 (1H, d, J=8), 7.43 (1H, d, J=8), 7.43 (1H,s), 7.11 (1H, d, J=8), 3.84 (3H, s), 2.56 (3H, s) ppm; ESMS calcd forC₂₁H₁₅F₃N₆O₄: 472; found: 473 (M+H).

Compound 1473-Methoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-4-nitro-benzamide

¹H NMR (CDCl₃): δ9.79 (1H, s), 8.74 (1H, s), 8.56 (1H, s), 7.99 (1H, d,J=9), 7.78 (1H, s), 7.57 (1H, d, J=9), 7.40 (1H, d, J=9), 7.25 (1H, s),7.10 (1H, d, J=9), 4.10 (3H, s), 3.91 (3H, s) ppm; ESMS calcd forC₂₁H₁₅F₃N₆O₅: 488; found: 489 (M+H).

Compound 1485-Chloro-2-fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, DMSO): δ 3.85 (3H,s), 7.15 (1H,d, J=8), 7.46 (3H,m),7.70 (1H,m), 7.84 (1H,m), 8.92 (1H, s), 9.48 (1H,s), 11.8 (1H,s) ppm;ESMS calcd for C₂₀H₁₂ClF₄N₅O₂: 465; found: 466 (M+H).

Compound 1492,3,4-Trifluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, DMSO) δ: 3.86 (3H,S), 7.15 (2H,d,J=8), 7.46 (2H,m),7.48 (1H,m), 8.93 (1H,s), 9.49 (1H,s), 11.83 (1H,s) ppm; ESMS calcd forC₂₀H₁₁F₆N₅O₂: 467; found: 468 (M+H).

Compound 1502-Fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-4-nitro-benzamide

¹H NMR (300 MHz, DMSO): δ 3.86 (3H,s), 7.15 (1H,d), 7.47 (2H,d, J=8),8.05 (1H,m), 8.23 (1H,m), 8.30 (1H, m), 8.93 (1H,s), 9.52 (1H,s), 12.05(1H,s) ppm; ESMS calcd for C₂₀H₁₂F₄N₆O₄: 476; found: 477 (M+H).

Compound 1512-Chloro-5-fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (DMSO): δ 11.90 (1H, s), 9.50 (1H, s), 8.90 (1H, s), 7.65 (2H, d,J=8), 7.46 (1H, s), 7.46 (2H, d, J=8), 7.13 (1H, s), 3.86 (1H, s) ppm;ESMS calcd for C₂₀H₁₂ClF₄N₅O₂: 465; found: 466 (M+H).

Compound 1525-Chloro-2-methoxy-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

¹H NMR (300 MHz, DMSO): δ 3.86 (3H,s), 3.95 (3H,s), 7.15 (1H,d, J=9),7.38 (1H,d, J=9), 7.46 (2H,d, J=9), 7.63 (1H,d, J=9), 7.75 (1H,s), 8.90(1H,s), 9.53 (1H,s), 11.24 (1H,s) ppm; ESMS calcd for C₂₁H₁₅ClF₃N₅O₃:477; found: 478 (M+H).

Compound 251-[5-(2,6-Difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester

Into a 1000 mL 3-necked round bottom flask, was placed a solution of4-aminobenzoic acid (20 g, 145.99 mmol) in methanol (600 mL). To theabove was added H₂SO₄ (30 mL) dropwise with stirring. The resultingsolution was stirred at reflux overnight. The reaction progress wasmonitored by TLC (EtOAc/PE=1:5). After completion, the volatilecomponents were removed under reduced pressure and the residue wasdissolved in 300 mL of water. Adjustment of the pH to 9 was accomplishedby the addition of and aqueous sat. Na₂CO₃ solution. The resultingsolution was extracted three times with 600 mL of EtOAc and the organiclayers were combined and dried over Na₂SO₄. Removal of the volatilecomponents under reduced pressure afforded the crude product methyl4-aminobenzoate (vii) (20.4 g, 93% yield) as a yellow solid which wasused directly in the next step without further purification.

Into a 250 mL roundbottom flask, was placed methyl 4-aminobenzoate (vii)(10 g, 66.23 mmol) followed by the addition of 2-chloropyrazine (75.9 g,665.79 mmol). The resulting solution was stirred at 150° C. for 4 hours.The reaction progress was monitored by TLC (EtOAc/PE=1:2). Aftercompletion, the reaction was cooled to room temperature and theundissolved material was filtered off. The filtration was dissolved in400 mL of water and the pH was adjustmented to 9 by the addition ofNa₂CO₃. The resulting solution was extracted four times with 800 mL ofEtOAc and the organic layers were combined and dried over Na₂SO₄.Removal of the solvent and volatile components from the organic layerunder reduced pressure provided the crude product methyl4-(pyrazin-2-ylamino)benzoate (viii) (13.6 g, 90% yield) as a yellowsolid which was used directly in the next step without furtherpurification.

Into a 500 mL 3-necked round bottom flask, was placed a solution ofmethyl 4-(pyrazin-2-ylamino)benzoate (viii) (25.0 g, 109.2 mmol) inH₂SO₄ (234 mL). This was followed by the addition of a solution of KNO₃(13.2 g, 131.0 mmol) in H₂SO₄ (78 mL) dropwise with stirring at −5-0° C.over a period of 15 minutes. The resulting solution was further stirredat this temperature for 2 hours then poured into 2000 mL of H₂O/ice. Theprecipitate was collected by filtration. The filter cake washed 3 timeswith 450 mL of water. The solid was then dissolved in 500 mL of EtOAc.The mixture was dried over Na₂SO₄ and concentrated by evaporation undervacuum using a rotary evaporator. This resulted in 24.2 g (81%) ofmethyl 3-nitro-4-(pyrazin-2-ylamino)benzoate (ix) as a yellow solidwhich was used directly in the next step without further purification.

Into a 500 mL round bottom flask, was placed a solution of methyl3-nitro-4-(pyrazin-2-ylamino)benzoate (ix) (10 g, 36.5 mmol) in dimethylformamide (DMF) (300 mL). To the mixture was added N-bromosuccinamide(NBS) (9.8 g, 54.8 mmol). The resulting solution was allowed to stirovernight at room temperature. The reaction mixture was then quenched bythe adding 600 mL of NaCl/H₂O then extracted three times with 250 mL ofEtOAc. The organic layers were combined then washed 1 time with 300 mLof NaHSO₃/H₂O and dried over Na₂SO₄. Removal of the solvent and volatilecomponents under reduced pressure resulted in 11.93 g (92%) of methyl4-(5-bromopyrazin-2-ylamino)-3-nitrobenzoate (x) as a yellow solid.

Into a 250 mL 3-necked roundbottom flask, was placed a solution ofmethyl 4-(5-bromopyrazin-2-ylamino)-3-nitrobenzoate (x) (5.0 g, 14.2mmol) in THF (75 mL). This was followed by the addition of a solution ofNH₄Cl (3.8 g, 71 mmol) in H₂O (25 mL). To the above was added Fe (4.0 g,71 mmol) in several batches, while warming to a temperature of 65° C.The resulting solution was allowed to react for 3 hours at 65° C. Thereaction progress was monitored by TLC (EtOAc/PE=1:2). Undissolvedmaterial was removed by filtration. The filtrate was extracted threetimes with 200 mL of EtOAc and the organic layers were combined anddired (Na₂SO₄). After removal of the solvent, the residue was separatedby silica gel chromatography eluting with a mixture of PE/EtOAc(starting at 10:1 and proceeding through 5:1, 3:1, and 2:1, v/v) toafford the product methyl 3-amino-4-(5-bromopyrazin-2-ylamino)benzoate(xi) (3.4 g, yield 74%) as a yellow solid.

Into a 100 mL round bottom flask, was placed a solution of methyl3-amino-4-(5-bromopyrazin-2-ylamino)benzoate (xi) (1.2 g, 3.73 mmol) indichloromethane (DCM) (50 mL). To this was added trifluoroaceticanhydride (TFAA) (8.10 mL). The resulting solution was stirred at 45° C.for 1 hour. The mixture was concentrated by evaporation under vacuumusing a rotary evaporator. Adjustment of the pH to 9 was accomplished bythe addition of K₂CO₃ (10%). The mixture was then extracted three timeswith 250 mL EtOAc (2×125 mL) and the combined EtOAc solution was driedover Na₂SO₄ and concentrated evaporation under vacuum. The residue wasthen taken up with toluene (80 mL). Toluene-4-sulfonic acid (TsOH) (370mg, 2.15 mmol) was then added. The resulting solution was allowed tostir at 100° C. for 3 hours. The resulting mixture washed 2 times with100 mL of H₂O. After being dried over Na₂SO₄, the solvent was removedunder reduced pressure. The residue was purified by eluting through asilica gel column with a 1:5 EtOAc/PE solvent system. This resulted in900 mg (60%) of methyl1-(5-bromopyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylate(xii) as a yellow solid.

Into a 50 mL 3-necked roundbottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of methyl1-(5-bromopyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylate(xii) (200 mg, 0.50 mmol) in 1,4-dioxane (10 mL). To this was added2,6-difluorobenzamide (235.5 mg, 1.50 mmol), followed by addition ofK₃PO₄.H₂O (500 mg, 1.48 mmol). CuI (11.7 mg, 0.06 mmol) was then addedto the mixture, followed by ethane-1,2-diamine (EDA) (3.2 mg, 0.05mmol). The resulting solution was allowed to stir for 45 minutes underreflux then diluted with 50 mL of H₂O and extracted three times with 300mL of EtOAc. The organic layers were combined then dried over Na₂SO₄ andconcentrated by evaporation under vacuum using a rotary evaporator. Theresidue was purified by eluting through a silica gel column with a 1:10EtOAc/PE solvent system to provide the final product methyl1-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylate(Compound 25) (10 mg, 4% yield) as a white solid.

¹H NMR (300 Hz, DMSO-d₆): δ 3.92 (s, 3H), 7.30 (t, 2H, J=8), 7.63 (m,1H), 7.66 (d, 1H, J=8), 8.10 (d, 1H, J=9), 8.54 (s, 1H), 8.97 (s, 1H),9.54 (s, 1H), 12.20 (s, 1H) ppm; ESMS calcd for C₂₁H₁₂F₅N₅O₃: 477;found: 478 (M+H).

Compound 28 was prepared by a method analogous to the method used toprepare Compound 25:

Compound 281-{5-[(3-Methyl-pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester

¹H NMR (300 Hz, DMSO-d₆): δ 2.27 (s, 3H), 3.92 (s, 3H), 7.55 (d, 1H,J=5), 7.71 (d, 1H, J=9)), 8.12 (d, 1H, J=9), 8.56-8.61 (m, 3H), 8.98 (s,1H), 9.55 (s, 1H), 11.88 (s, 1H) ppm; ESMS calcd for C₂₁H₁₅F₃N₆O₃: 456;found: 457 (M+H).

Compound 1532,6-Difluoro-N-[5-(5-oxazol-2-yl-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide

Into a 100 mL roundbottom flask, was placed a solution of methyl1-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylate(Compound 25) (200 mg, 0.42 mmol, 1.00 equiv) in MeOH (10 mL). To themixture was added NaOH (2.5M) (12 mL, 3.00 equiv). The resultingsolution was allowed to stir at room temperature for 1 hour. Adjustmentof the pH to 1-2 was accomplished by the addition of HCl (10%). Theprecipitated product was collected by filtration and dried in an ovenunder reduced pressure. This resulted in 140 mg (67%) of methyl1-[5-(2,6-Difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid (xiii) as a white solid.

Into a 50 mL roundbottom flask, was placed a solution of1-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylicacid (xiii) (50 mg, 0.11 mmol, 1.00 equiv) in DCM (15 ml) and DMF (1drop). To the above stirred solution was added oxalyl dichloride (70 mg,0.55 mmol, 5.00 equiv) dropwise at 0° C. The resulting solution wasallowed to stir at 0° C. for 4 hours then was concentrated byevaporation under vacuum using a rotary evaporator. The residue was thentaken up by DCM (10 ml) and then add dropwise to a stirred solution ofEt₃N (40 mg, 3.00 equiv) and 2,2-diethoxyethanamine (15 mg, 0.11 mmol,1.00 equiv) in DCM (10 mL) at 0° C. The resulting solution was allowedto stir overnight at room temperature, then washed with H₂O (2×100 mL)and dried over Na₂SO₄. Removal of the solvent and volatile componentsafforded the crude product1-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid (2,2-diethoxy-ethyl)-amide (xiv) (50 mg, 64% yield) as a yellowsolid that was used directly in the next step.

Into a 50 mL roundbottom flask, was placed a solution of1-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid (2,2-diethoxy-ethyl)-amide (xiv) (50 mg, 0.09 mmol, 1.00 equiv) inCH₃SO₃H (3 g). To the mixture was added P₂O₅ (80 mg, 0.56 mmol, 5.00equiv). The resulting solution was allowed to stir at 130° C. for 3 h,then was diluted with ice water and extracted three times with 150 mL ofEtOAc. The organic layers were combined and dried over Na₂SO₄. Afterremoval of the solvent and volatile components, the residue was purifiedby eluting through a silica gel column with first a 1:3 and then 1:2EtOAc/PE solvent system to provide2,6-difluoro-N-[5-(5-oxazol-2-yl-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide(Compound 153) (5 mg, 12% yield) as a white solid.

¹H NMR (300 Hz, DMSO-d₆): δ 7.12 (t, 2H, J=9), 7.28-7.30 (m, 1H), 7.46(d, 1H, J=9), 7.54-7.59 (m, 1H), 7.79 (s, 1H), 8.25 (d, 1H, J=9), 8.58(s, 1H), 8.64 (s, 2H), 9.84 (s, 1H) ppm; ESMS calcd for C₂₂H₁₁F₅N₆O₂:486; found: 487 (M+H).

Example 2 Inhibition of IL-2 Production

Jurkat cells were placed in a 96 well plate (0.5 million cells per wellin 1% FBS medium) then a test compound of this invention was added atdifferent concentrations. After 10 minutes, the cells were activatedwith PHA (final concentration 2.5 μg/mL) and incubated for 20 hours at37° C. under CO₂. The final volume was 200 μL. Following incubation, thecells were centrifuged and the supernatants were collected and stored at−70° C. prior to assaying for IL-2 production. A commercial ELISA kit(IL-2 Eli-pair, Diaclone Research, Besancon, France) was used to detectproduction of IL-2, from which dose response curves were obtained. TheIC₅₀ value was calculated as the concentration at which 50% of maximumIL-2 production after stimulation was inhibited versus a non-stimulationcontrol. As can be seen from the table below, certain compounds of theinvention inhibited IL-2 in the nanamolar range.

Compound No. IL-2 (IC₅₀) 1 6 nM 3 79 nM 5 20 nM 7 33 nM 9 55 nM 10 12 nM25 29 nM 28 112 nM 37 103 nM 41 396 nM 46 >1000 nM 73 >1000 nM 85 37 nM86 150 nM 87 >1000 nM 88 101 nM 89 >1000 nM 90 >1000 nM 91 384 nM 92 17nM 93 181 nM 94 78 nM 95 489 nM 96 91 nM 97 307 nM 98 104 nM 99 52 nM100 132 nM 101 96 nM 102 >1000 nM 103 >1000 nM 104 929 nM 105 >1000 nM106 2 nM 107 18 nM 108 57 nM 109 279 nM 110 19 nM 111 >1000 nM 112 173nM 113 22 nM 114 88 nM 115 >1000 nM 116 170 nM 117 81 nM 118 40 nM 11950 nM 120 295 nM 121 >1000 nM 122 73 nM 123 >1000 nM 124 >1000 nM 125780 nM 126 >1000 nM 127 105 nM 128 187 nM 129 >1000 nM 130 130 nM 131331 nM 132 >1000 nM 133 >1000 nM 134 >1000 nM 135 103 nM 136 >1000 nM137 714 nM 138 83 nM 139 >1000 nM 140 192 nM 141 >1000 nM 142 324 nM 143178 nM 144 >1000 nM 145 99 nM 146 18 nM 147 >1000 nM 148 98 nM 149 88 nM150 126 nM 151 27 nM 152 >1000 nM 153 15 nM

Inhibition of other cytokines, such as IL-4, IL-5, IL-13, GM-CSF, TNF-α,and INF-γ, can be tested in a similar manner using a commerciallyavailable ELISA kit for each cytokine.

Example 3 Patch Clamp Studies of Inhibition of I_(CRAC) Current in RBLCells, Jurkat Cells, and Primary T Cells

In general, a whole cell patch clamp method was used to examine theeffects of a compound of the invention on a channel that mediatesI_(crac). In such experiments, a baseline measurement was establishedfor a patched cell. Then a compound to be tested was perfused (orpuffed) to cells in the external solution and the effect of the compoundon I_(crac) was measured. A compound that modulates I_(crac) (e.g.,inhibits) is a compound that is useful in the invention for modulatingCRAC ion channel activity.

1) RBL Cells

Cells

Rat basophilic leukemia cells (RBL-2H3) were grown in DMEM mediasupplemented with 10% fetal bovine serum in an atmosphere of 95% air/5%CO₂. Cells were seeded on glass coverslips 1-3 days before use.

Recording Conditions

Membrane currents of individual cells were recorded using the whole-cellconfiguration of the patch clamp technique with an EPC10 (HEKAElectronik, Lambrecht, Germany). Electrodes (2-5 MΩ in resistance) werefashioned from borosilicate glass capillary tubes (Sutter Instruments,Novato, Ca). The recordings were done at room temperature.

Intracellular Pipette Solution

The intracellular pipette solution contained Cs-Glutamate 120 mM; CsCl20 mM; CsBAPTA 10 mM; CsHEPES 10 mM; NaCl 8 mM; MgCl₂ 1 mM; IP3 0.02 mM;pH=7.4 adjusted with CsOH. The solution was kept on ice and shieldedfrom light before the experiment was preformed.

Extracellular Solution

The extracellular solution contained NaCl 138 mM; NaHEPES, 10 mM; CsCl10 mM; CaCl₂ 10 mM; Glucose 5.5 mM; KCl 5.4 mM; KH₂PO₄ 0.4 mM;Na₂HPO₄.H₂O 0.3 mM at pH=7.4 adjusted with NaOH.

Compound Treatment

Each compound was diluted from a 10 mM stock in series using DMSO. Thefinal DMSO concentration was always kept at 0.1%.

Experimental Procedure

I_(CRAC) currents were monitored every 2 seconds using a 50 msecprotocol, where the voltage was ramped from −100 mV to +100 mV. Themembrane potential was held at 0 mV between the test ramps. In a typicalexperiment, the peak inward currents developed within 50-100 seconds.Once the I_(CRAC) currents were stabilized, the cells were perfused witha test compound in the extracellular solution. At the end of anexperiment, the remaining I_(CRAC) currents were then challenged with acontrol compound (SKF96365, 10 μM) to ensure that the current couldstill be inhibited.

Data Analysis

The I_(CRAC) current level was determined by measuring the inwardcurrent amplitude at −80 mV of the voltage ramp in an off-line analysisusing MATLAB. The I_(CRAC) current inhibition for each concentration wascalculated using peak amplitude in the beginning of the experiment fromthe same cell. The IC₅₀ value and Hill coefficient for each compound wasestimated by fitting all the individual data points to a single Hillequation.

Results

The table below shows the concentration of a compound of the inventionwhich inhibits 50% of the I_(CRAC) current in RBL cells. As can be seenfrom the data in the table, a representative compound of the inventioninhibit I_(CRAC) current at concentration of 60 nM.

Compound Number IC₅₀ 1 60 nM SKF96365 4 μM

2) Jurkat Cells

Cells

Jurkat T cells are grown on glass coverslips, transferred to therecording chamber and kept in a standard modified Ringer's solution ofthe following composition: NaCl 145 mM, KCl 2.8 mM, CsCl 10 mM, CaCl₂ 10mM, MgCl₂ 2 mM, glucose 10 mM, HEPES-NaOH 10 mM, pH 7.2.

Extracellular Solution

The external solution contains 10 mM CaNaR, 11.5 mM glucose and a testcompound at various concentrations.

Intracellular Pipette Solution

The standard intracellular pipette solution contains: Cs-glutamate 145mM, NaCl 8 mM, MgCl₂ 1 mM, ATP 0.5 mM, GTP 0.3 mM, pH 7.2 adjusted withCsOH. The solution is supplemented with a mixture of 10 mM Cs-BAPTA and4.3-5.3 mM CaCl₂ to buffer [Ca²⁺]i to resting levels of 100-150 nM.

Patch-clamp Recordings

Patch-clamp experiments are performed in the tight-seal whole-cellconfiguration at 21-25° C. High-resolution current recordings areacquired by a computer-based patch-clamp amplifier system (EPC-9, HEKA,Lambrecht, Germany). Sylgard®-coated patch pipettes typically haveresistances between 24 MΩ after filling with the standard intracellularsolution. Immediately following establishment of the whole-cellconfiguration, voltage ramps of 50 ms duration spanning the voltagerange of −100 to +100 mV are delivered from a holding potential of 0 mVat a rate of 0.5 Hz over a period of 300 to 400 seconds. All voltagesare corrected for a liquid junction potential of 10 mV between externaland internal solutions. Currents are filtered at 2.3 kHz and digitizedat 100 μs intervals. Capacitive currents and series resistance aredetermined and corrected before each voltage ramp using the automaticcapacitance compensation of the EPC-9.

Data Analysis

The very first ramps before activation of I_(CRAC) (usually 1 to 3) aredigitally filtered at 2 kHz, pooled and used for leak-subtraction of allsubsequent current records. The low-resolution temporal development ofinward currents is extracted from the leak-corrected individual rampcurrent records by measuring the current amplitude at −80 mV or avoltage of choice.

Compounds of the invention are expected to inhibit I_(CRAC) current inJurkat cells.

3) Primary T Cells

Preparation of Primary T Cells

Primary T cells are obtained from human whole blood samples by adding100 μL of RosetteSep® human T cell enrichment cocktail to 2 mL of wholeblood. The mixture is incubated for 20 minutes at room temperature, thendiluted with an equal volume of PBS containing 2% FBS. The mixture islayered on top of RosetteSep® DM-L density medium and then centrifugedfor 20 minutes at 1200 g at room temperature. The enriched T cells arerecovered from the plasma/density medium interface, then washed with PBScontaining 2% FBS twice, and used in patch clamp experiments followingthe procedure described for RBL cells.

Compounds of the invention are expected to inhibit I_(CRAC) current inhuman primary T cells.

Example 4 Inhibition of Multiple Cytokines in Primary Human PBMCs

Peripheral blood mononuclear cells (PBMCs) are stimulated withphytohemagglutinin (PHA) in the presence of varying concentrations ofcompounds of the invention or cyclosporine A (CsA), a known inhibitor ofcytokine production. Cytokine production is measured using commerciallyavailable human ELISA assay kits (from Cell Science, Inc.) following themanufacturers instructions.

The compounds of the invention are potent inhibitors of IL-2, and areexpected to be potent inhibitors of IL-4, IL-5, IL-13, GM-CSF, INF-γ andTNF-α in primary human PBM cells. In addition, compounds of theinvention are not expected to inhibit the anti-inflammatory cytokine,IL-10.

Example 5 Inhibition of Degranulation in RBL Cells

Procedure:

The day before the assay is performed, RBL cells, that had been grown toconfluence in a 96 well plate, are incubated at 37° C. for at least 2hours. The medium is replaced in each well with 100 μL of fresh mediumcontaining 2 μg/mL of anti-DNP IgE.

On the following day, the cells are washed once with PRS (2.6 mM glucoseand 0.1% BSA) and 160 μL of PRS was added to each well. A test compoundis added to a well in a 20 μL solution at 10× of the desiredconcentration and incubated for 20 to 40 minutes at 37° C. 20 μL of 10×mouse anti-IgE (10 μL/mL) is added. SKF96365 is used as a positivecontrol. Maximum degranulation typically occurs between 15 to 40 minutesafter addition of anti-IgE.

Results:

Compounds of the invention are expected to inhibit degranulation of RBLcells.

Example 6 Inhibition of Chemotaxis in T Cells

T-cell Isolation:

Twenty ml aliquots of heparinized whole blood are subjected to densitygradient centrifugation on Ficoll Hypaque. The buffy coat layersrepresenting peripheral blood mononuclear cells (PBMCs) containinglymphocytes and monocytes are washed once, resuspended in 12 ml ofincomplete RPMI 1640 and then placed in gelatin-coated T75 cultureflasks for 1 hr at 37° C. The non-adherent cells, representingperipheral blood lymphocytes (PBLs) depleted of monocytes, areresuspended in complete RPMI media and placed in loosely packedactivated nylon wool columns that had been equilibrated with warm media.After 1 hr at 37° C., the non-adherent T cell populations are eluted bywashing of the columns with additional media. The T cell preparationsare centrifuged, resuspended in 5 ml of incomplete RPMI, and countedusing a hemocytometer.

Cell Migration Assay:

Aliquots of each T cell preparation are labeled with Calcien AM(TefLabs) and suspended at a concentration of 2.4×10⁶/ml inHEPES-buffered Hank's Balanced Salt Solution containing 1.83 mM CaCl₂and 0.8 mM MgCl₂, pH 7.4 (HHBSS). An equal volume of HHBSS containing 0,20 nM, 200 nM or 2000 nM of compound 1 or 20 nM EDTA is then added andthe cells are incubated for 30 min at 37° C. Fifty μl aliquots of thecell suspensions (60,000 cells) are placed on the membrane (pore size 5μm) of a Neuroprobe ChemoTx 96 well chemotaxis unit that had beenaffixed over wells containing 10 ng/ml MIP-1α in HHBSS. The T cells areallowed to migrate for 2 hr at 37° C., after which the apical surface ofthe membrane is wiped clean of cells. The chemotaxis units are thenplaced in a CytoFlour 4000 (PerSeptive BioSystems) and the fluorescenceof each well is measured (excitation and emission wavelengths of 450 and530 nm, respectively). The number of migrating cells in each well isdetermined from a standard curve generated from measuring thefluorescence of serial two-fold dilutions of the labeled cells placed inthe lower wells of the chemotaxis unit prior to affixing the membrane.

Results: Compounds of the invention are expected to be inhibitory to thechemotactic response of porcine T cells and in human T cells.

Example 7 Inhibition of Delayed-Type Hypersensitivity (DTH) Reaction inRats

Lewis rats (n=7 each group) were sensitized with chicken ovalbumin (OVA;Sigma, A5503) and complete Freund's adjuvant (CFA; Sigma F5881) wasinjected into tail base by s.c. on day 0. On day 7, the animals werechallenged with ovalbumin (OVA) on their right ears. Test compounds(Compounds 1 and 10), positive control (cyclosporine A (CsA), andvehicle were given to animals before (−2 hr) and after (+3 hr and +9 hr)the challenge (0 hr). Animals were then monitored for ear thickness andweight in comparison with saline-treated left ears 24 hr afterchallenge.

Test Compounds

Compounds 1 and 10 were prepared in vehicle solution (20% Vitamin E TPGSand 80% PEG-8).

Animals

Female Lewis rats, 6-8 weeks of age, were obtained from Charles RiverLaboratories and permitted to acclimate for one week prior toexperimental procedures. Rodents were allowed water and food ad libitum.Animals were housed in accordance with the Institutional Animal Care andUse Committee (IACUC), and experiments were performed in compliance withIACUC guidelines.

Measurement of Ear Thickness and Ear Weight

Rat ears were measured with a dial thickness gauge (Mitutoyo gauge #8,Mitutoyo, USA). The swelling response was calculated by subtracting theear thickness before challenge (baseline) from that of the same earafter challenge. To measure the ear weight, both left and right ears ofeuthanized rats were punched out with cork holer, the ear weight changewas calculated by subtracting the saline-treated left ear weight fromthat of the OVA-challenged right ear weight.

Results

Delayed-type hypersensitivity is an in vivo T cell-dependent immuneresponse manifested as an inflammatory reaction that reaches peakintensity 24 hr after OVA challenge. To determine the immunosuppressiveeffect of Compounds 1 and 10 in the rat DTH reaction, groups of rats(n=7) were administered with either vehicle, Compound 1 or Compound 10,orally three times, starting 2 hr before ear challenge, and 3 and 9 hrafter ear challenge. 15 mg/kg Compound 1 significantly inhibited earweight (see FIGS. 1 and 2) and ear thickness (see FIGS. 3 and 4).Compound 10 had an even stronger effect on reducing ear thickness andweight after challenge than Compound 1, as can be see in the tablebelow. Compound 10 reduced ear thickness and weight after challenge morethan dosing with cyclosporine A which is an immunosuppressant that wasused as a positive control.

Comparison of in vivo rat DTH activity Dose Inhibition of gross change(%)^((a)) (mg/kg) Ear Ear thickness Compound in DTH weight (mg) (mm)Comp. 10 15 24 15 Comp. 1 15 79 77 CsA 15 64 61 ^((a))Mean values ofpercentage inhibition seen in animals relative to vehicle-treated group,assessed by changes in ear weight and thickness.

REFERENCES

-   Meingassner J. G et al. (1997) A noval anti-inflammatory drug, SDZ    ASM 981, for the topical and oral treatment of skin diseases: in    vivo pharmacology. British J. Dermatology 137: 568.-   Lou Y. et al. (2000) Delayed-type hypersensitivity, Current    protocols in immunology p 4.5.1

All publications, patent applications, patents, and other documentscited herein are incorporated by reference in their entirety. In case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting in any way.

From the foregoing description, it will be apparent that variations andmodifications may be made to the invention described herein. Suchembodiments are also within the scope of the following claims.

We claim:
 1. A compound selected from the group consisting of:2,6-Difluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide;3,5-Difluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-isonicotinamide;3-Fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-isonicotinamide;N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl-isonicotinamide;2-Fluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide;N-[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-benzamide; 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amide;N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2,6-difluoro-benzamide;N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide;N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-fluoro-isonicotinamide;N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl-isonicotinamide;N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-fluoro-benzamide;N-[5-(5-Ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-2-methyl-benzamide;4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid[5-(5-ethoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amide;1-[5-(2,6-Difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;1-{5-[(3,5-Difluoro-pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;1-{5-[(3-Fluoro-pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;1-{5-[(3-Methyl-pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;1-[5-(2-Fluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;1-[5-(2-Methyl-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester; 1-{5-[(4-Methyl- [1,2,3]thiadiazole-5-carbonyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;(2,6-Difluoro-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine;(3,5-Difluoro-pyridin-4-ylmethyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine;(3-Fluoro-pyridin-4-ylmethyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine;[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(3-methyl-pyridin-4-ylmethyl)-amine;(2-Fluoro-benzyl)-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine;[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-benzyl)-amine;[5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(4-methyl-[1,2,3]thiadiazol-5-ylmethyl)-amine;1-[5-(2,6-Difluoro-benzylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;1-{5-[(3,5-Difluoro-pyridin-4-ylmethyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;1-{5-[(3-Fluoro-pyridin-4-ylmethyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;1-{5-[(3-Methyl-pyridin-4-ylmethyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;1-[5-(2-Fluoro-benzylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;1-[5-(2-Methyl-benzylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;1-{5[(4-Methyl-[1,2,3]thiadiazol-5-ylmethyl)-amino]-pyrazin-2-yl}-2-trifluoromethyl-1H-benzoimidazole-5-carboxylicacid methyl ester;2,6-Difluoro-N-[5-(6-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide;N-[5-(6-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-3-methyl-isonicotinamide;4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid[5-(6-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amide;(2,6-Difluoro-benzyl)-[5-(6-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-amine;[5-(6-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(3-methyl-pyridin-4-ylmethyl)-amine;or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and acompound of claim
 1. 3. A method of inhibiting immune cell activationcomprising administering to the cell a compound of claim
 1. 4. Themethod of claim 3, wherein immune cell activation is inhibited in asubject by administering the compound to the subject.
 5. The method ofclaim 4, wherein the subject is human.
 6. A method of inhibitingcytokine production in a cell, comprising administering to the cell acompound of claim
 1. 7. The method of claim 6, wherein cytokineproduction is inhibited in a subject by administering the compound tothe subject.
 8. The method of claim 7, wherein the subject is human. 9.The method of claim 7, wherein the cytokine is selected from the groupconsisting of IL-2, IL-4, IL-5, IL-13, GM-CSF, IFN-α, TNF-α, andcombinations thereof.
 10. The method of claim 9, wherein the cytokine isIL-2.
 11. A method of modulating an ion channel in a cell, wherein theion channel is involved in immune cell activation, comprisingadministering to the cell a compound of claim
 1. 12. The method of claim11, wherein the ion channel is in a subject and it is modulated byadministering the compound to the subject.
 13. The method of claim 12,wherein the subject is human.
 14. The method of claim 12, wherein theion channel is a Ca²⁺-release-activated Ca²⁺ channel (CRAC).
 15. Amethod of inhibiting mast cell degranulation, comprising administeringto the cell a compound of claim
 1. 16. The method of claim 15, whereinmast cell degranulation is inhibited in a subject by administering thecompound to the subject.
 17. The method of claim 16, wherein the subjectis human.